REVIEWS

Mechanisms of tissue and cell-type

specificity in heritable traits
and diseases
Idan Hekselman1 and Esti Yeger-Lotem   1,2*
Abstract | Hundreds of heritable traits and diseases that are caused by germline aberrations in
ubiquitously expressed genes manifest in a remarkably limited number of cell types and tissues
across the body. Unravelling mechanisms that govern their tissue-specific manifestations is
critical for our understanding of disease aetiologies and may direct efforts to develop treatments.
Owing to recent advances in high-throughput technologies and open resources, data and tools
are now available to approach this enigmatic phenomenon at large scales, both computationally
and experimentally. Here, we discuss the large prevalence of tissue-selective traits and diseases,
describe common molecular mechanisms underlying their tissue-selective manifestation and
present computational strategies and publicly available resources for elucidating the molecular
basis of their genotype–phenotype relationships.

Heritable traits and

diseases
Phenotypes with a heritable
monogenic or polygenic
component due to inherited or
de novo germline aberrations
present throughout the body.
Germline aberrations
Aberrations (inherited or
de novo) that are common to
all cells harbouring the
individual’s genome.
Causal genes
Genes containing a variant that
was found to lead to disease.
1
Department of Clinical
Biochemistry & Pharmacology,
Faculty of Health Sciences,
Ben-Gurion University of the
Negev, Be’er-Sheva, Israel.
2
National Institute for
Biotechnology in the Negev,
Ben-Gurion University,
Be’er-Sheva, Israel.
*e-mail: estiyl@bgu.ac.il
https://doi.org/10.1038/
s41576-019-0200-9
Heritable traits and diseases are commonly considered
in terms of their affected organs, tissues or cell types.
For example, cystic fibrosis (CF) brings to mind the
respiratory system, whereas Parkinson disease (PD)
is linked with dopaminergic neurons. More generally,
analysis of over 1,200 Mendelian diseases shows that
most Mendelian diseases manifest clinically in a highly
tissue-specific manner (Fig. 1a). Tissue-specific manifes-
tation is expected when caused by somatic aberrations
localized to particular tissues (Box 1); yet, it is intrigu-
ing in heritable traits and diseases as these are caused
by  germline aberrations present throughout the body1.
An intuitive explanation for the tissue specificity of
heritable traits and diseases is that their causal genes are
expressed physiologically in a limited number of tissues.
However, genes causal for these traits and diseases are
often expressed widely throughout the human body1–3
(Fig.  1b) without tissue-specific preference (Fig.  1c) .
Do we understand what, then, leads to the tissue-specific
manifestation of various heritable traits and diseases?
The genetic diagnosis of heritable diseases, namely
identifying the causal gene or variant, has been greatly
facilitated by clinical usage of next-generation sequenc-
ing, which is executed routinely and at large scales4.
By contrast, the molecular understanding of disease
aetiologies, namely identifying how the causal aberra-
tion leads to disease symptoms, currently lags behind.
The elucidation of disease aetiologies typically requires
focused, low-throughput experiments that were tailored
to the disease in question. Consequently, pathological
mechanisms have remained elusive even for well-studied
heritable diseases that were genetically solved decades
ago, including Gaucher disease5, Huntington disease6,
PD7–9 and cardiomyopathies10. Identifying the mecha­
nisms that underlie the tissue-selective pathogenesis
could provide an important first step towards elucidating
disease aetiologies. Since these mechanisms could high-
light components that are critical for the normal physiol-
ogy of the disease-related tissue11 or, alternatively, disease
modifiers that contribute to the resilience of unaffected
tissues, they could open new therapeutic directions.
The large number of tissue-selective heritable diseases
that are yet to be molecularly deciphered, as well as the
important implications of their elucidation for basic sci-
ence and therapeutic strategies, call for new approaches
for their investigation. A stepping-stone in the devel-
opment of such approaches is the unprecedented
scale of available molecular profiles of human tissues,
organs and cell types (henceforth collectively denoted
as tissues for brevity). Since the beginning of the new
millennium, diverse human tissues have been interro-
gated via multiple omics profiling technologies (Table 1).
Transcriptomic profiling was first applied to a few sam-
ples per tissue12,13. With the advent of next-generation
sequencing, RNA sequencing (RNA-seq) of physiolo­
gical tissues from hundreds of human donors was car-
ried out by the Genotype–Tissue Expression (GTEx)
project14 and others15. Most recently, single-cell RNA-seq
(scRNA-seq) datasets of human tissues are becoming
available through, for example, the Human Cell Atlas16.
Several ensuing projects arose to aggregate available data
from consortia-based projects and others. For example,

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a 1,200 Fig. 1 | The tissue selectivity of heritable diseases and

traits and their associated genes. a | Germline aberrations
that underlie diseases are present throughout the body
(red diamonds) yet often manifest clinically in few tissues

Number of Mendelian diseases

(red star, pointed by an arrow), as shown for 1,252 Mendelian
800 diseases2,44. b | In contrast to the tissue specificity of
diseases, disease-associated genes are typically expressed
widely across tissues. The number of tissues expressing a
gene is shown for 15,515 protein-coding genes expressed
in any tissue (blue), for 1,044 genes causal for the 1,252
400
Mendelian diseases shown in part a (red) and for 402 genes
significantly associated with 20 complex traits47 (yellow).
Expression values were downloaded from the Genotype–
Tissue Expression (GTEx) portal and refer to GTEx v.7.
0 Only genes whose median expression level in a tissue
1 2 3 4 5 6–30 exceeded 10 transcripts per million (TPM) were considered
Number of disease-manifesting tissues to be expressed in that tissue. Subregions of the same tissue
Unaffected tissues were collated and appear as one (relevant for brain, heart,
Disease-manifesting tissue artery, cervix, colon, skin and oesophagus tissues), and
the maximal expression level was taken. Although the
distributions partially depend on the expression level
threshold chosen154, the conclusion of most genes being
b Expressed genes
expressed across multiple tissues is robust for alternative
30
Protein-coding expression level cut-offs of 5 and 15 TPM (see Supplementary
Mendelian disease genes information for further details on the data analysis, including
Expressed genes (%)

Trait-associated the effects of different expression level cut-offs). c | Most

20 disease-associated genes are not preferentially expressed
in any tissue. The distribution of genes preferentially
expressed in 0, 1, 2 or at least 3 tissues is shown for protein-
10 coding genes (left), genes causal for Mendelian diseases
(middle) and genes significantly associated with complex
traits (right). Preferential expression was derived from ref.51,
and similarly defined as genes with a preferential score
0 >2 in at least one tissue according to data from GTEx v.6
2

10

0
1–

3–

5–

7–

–1

–1

–1

–1

–2

–2

–2

–2

–2

–3

(see Supplementary information for further details on the

9–

11

13

15

17

19

21

23

25

27

29

Number of expressing tissues data analysis).

These collaborative efforts have enabled a change

c Preferentially expressed genes
Protein-coding
1 2
Mendelian disease genes
>3 0 1 2 >3 0 1
recount2 reprocessed ~70,000 human RNA-seq sam-
ples17, and the volume of sequencing and array data in
ArrayExpress and Gene Expression Omnibus continues
to grow. Tissue profiling has been extended to additional
omics assays. Proteomic profiling of tissues was carried
out by the Human Protein Atlas (HPA) consortium18
and others19. Large-scale profiling of DNA regulatory
elements and chromatin modifications mostly from
cell lines was carried out by the Encyclopedia of DNA
Elements (ENCODE)20 and Functional Annotation
of the Mammalian Genome (FANTOM5)21, whereas
Roadmap Epigenomics performed similar chroma-
tin profiling but with a more overt focus on primary
tissues rather than cell lines22, with other efforts aimed at
creating tissue chromatin contact maps23.
in the way disease aetiologies can be approached.
Trait-associated In addition to studying them in the context of the dis-
eased tissue, comparative analyses of disease-related
versus unaffected tissues can be performed. Indeed,
emerging experimental and computational methods
are starting to provide explanatory insights for several
diseases1,2,11,24–31. Owing to open data resources14,18,24,25,32,33
and to the enthusiasm with which they have been met by
the computational community, data and tools are now
available to apply these methods and others to many
2 >3 0
diseases. In this Review, we first discuss current knowl-
edge of the prevalence of tissue-selective manifestation
of hereditary diseases and its limitations, followed by
a description of the known mechanisms by which tis-
sue selectivity is mediated. Finally, we discuss the open
resources, designed for non-computational investigators,
to facilitate the exploration of the molecular mechanisms
underlying the numerous traits and diseases that await
resolution.
Tissue selectivity is prevalent among diseases
Extensive RNA-seq and proteomic analyses across
human tissues have repeatedly revealed that, whereas tis-
sues differ greatly in their morphology and functions, the
majority of the genes and proteins are expressed widely
across the human body and only a minority are tissue
specific14,18,34. In particular, the subset of protein-coding

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Box 1 | The tissue specificity of somatic mutations
Somatic mutations tend to vary in numbers and patterns between tissues.
These variations were attributed to differences in the exposure of each tissue to
mutation-inducing substances or microenvironmental factors. For example, lungs are
exposed to tobacco smoke, which elicits lung cancers, whereas skin is exposed to
ultraviolet light, which elicits melanoma. More recently, the difference in cell division
rates, and consequently in the rates of replication errors, was revealed as a major source
for somatic variation149, as a strong correlation between stem cell division rate and
cancer incidence was shown across cancers and countries149.
The question of whether the impact of specific somatic mutations tends to be tissue
specific has been thoroughly studied in the context of cancer150. It was shown that,
whereas mutation of certain cancer-driving genes, such as TP53 (which encodes p53)
and KRAS, lead to cancers across several tissues, many more cancer drivers lead to
cancers in specific tissues151. As has been observed for heritable disorders, despite
the pathological effects being frequently tissue specific, the cancer driver genes
affected by the mutations are rarely expressed in a tissue-specific manner1,152,153.
Multiple mechanistic explanations have been suggested for this phenomenon150 such
as differences in the epigenetic landscape across tissues140. Nevertheless, how somatic
mutations affect certain tissues but not others is still considered an important open
question in cancer research140.
genes that are causal for hereditary diseases is not more
tissue specific than protein-coding genes in general
(Fig. 1b). Given their widespread expression, it is intrigu-
ing to investigate the extent to which genetic diseases
themselves are tissue selective.
According to the well-established database of Online
Mendelian Inheritance in Man (OMIM)35, over 7,000
Mendelian disorders have been identified so far. More
than half (3,879 disorders) were fully diagnosed geneti-
cally and map to variation in 3,910 protein-coding genes.
The tissues that are clinically affected by each disease are
generally recognized by signs and symptoms presented
by patients. Until the last decade, knowledge of tissue
associations was not organized in a structured manner
in publicly available databases. This gap has been
bridged by computational techniques, for example, by
Pathogenic tissues applying text-mining techniques to abstracts in PubMed
The tissues that elicit the to identify significant co-mentioning of disorders and
disease. tissues1. The association between diseases and clinically
affected tissues became more readily accessible with the
Complex traits
Traits caused by variations in
creation of disease-oriented public databases, such as
multiple genes or non-coding the Human Phenotype Ontology (HPO)36 and Disease
genomic regions potentially in Ontology37, which record phenotypic abnormalities for
combination with other factors thousands of diseases (Table 2). Efforts to further expand
such as environmental
and refine the knowledge of tissues affected by diseases
exposure or lifestyle.
are still ongoing38.
Genome-wide association The association between diseases and affected tissues
studies is not always straightforward. Diseases may have sub-
(GWAS). Studies that scan tle phenotypes in tissues other than the main affected
genetic variants across
individuals to identify variants
tissues, which might escape notice. For example, one
that are significantly associated of the earliest symptoms of several neurodegenerative
with a trait (the variants are disorders that can be easily missed is the loss of smell39.
known as risk alleles when they Likewise, certain tissues might be affected in only a sub-
are associated with disease
set of the patients. A well-known example is CF, where
occurrence).
patients present large variability in organ involvement,
Monogenic including variable lung dysfunction, male infertility and
A trait caused by variation in a pancreatic insufficiency40. Similarly, certain patients
single gene. with familial mutations in the BRCA1 or BRCA2 genes
Susceptible tissue
develop breast cancer, whereas others develop ovarian
The tissue that manifests a trait cancer41. Additionally, affected tissues might differ from
or disease. the actual  pathogenic tissues where damage initiated.
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In endocrine disorders, damage in hormone-producing
cells, such as the insulin-producing pancreatic β-cells
in the case of type 1 diabetes mellitus, manifests clini-
cally in remote tissues harbouring hormone receptors42.
Likewise, in Bartter syndrome, decreased absorption
of ions in the middle part of the nephron overloads
α-intercalated cells of the distal collecting duct 43.
Altogether, since pathologies are not typically studied
holistically across a range of tissues and developmen-
tal states, current knowledge of the tissue selectivity of
genetic diseases might be noisy and partial due to clinical
and/or technical complexities.
Notwithstanding these caveats, multiple large-scale
analyses of associations between diseases and affected tis-
sues were conducted across various subsets of Mendelian
diseases. These analyses, which were based on a combi-
nation of expert curation and text mining of PubMed1,2
and OMIM44, have repeatedly shown that Mendelian
diseases have a clear tendency for tissue-specific mani­
festation (Fig. 1a). Putting this phenomenon in an evo-
lutionary context, tissue-specific diseases might be less
detrimental than diseases that broadly affect the body,
and thus more likely to be heritable. Tissue specificity
is also common among complex diseases and traits, of
which neurodegenerative disorders, cardiovascular dis-
eases, autoimmune diseases and systolic blood pressure
are just a few examples45–47. In fact, tissue specificity
has been leveraged repeatedly to illuminate the aetiol-
ogy of  complex traits and to interpret genetic findings
obtained via genome-wide association studies (GWAS)45.
In summary, although our knowledge of the full list of
affected tissues per disease is partial, affected tissues
remain a rather small subset compared to the broad
expression of the underlying causal genes (Fig. 1b). Why,
then, are only certain tissues affected by an inherent
aberration, while other tissues that express the aberrant
gene remain robust? In the next section, we discuss sev-
eral molecular mechanisms that elicit or contribute to the
tissue-specific manifestation of monogenic and complex
diseases.
Molecular mechanisms of tissue specificity
Why does a disease that stems from a germline aberra-
tion manifest in a tissue-specific manner? A main claim
is that the susceptible tissue, which clinically manifests
the disease, has a signifying characteristic function or
feature that is disease related. For example, liver and
muscle, where glycogen metabolism is carried out, are
affected in glycogen storage diseases; long-lived neu-
rons are sensitive to the cumulative effect of protein
misfolding; and skin is exposed to ultraviolet radiation
and therefore prone to DNA damage and melanoma.
However, such clear associations between tissue features
and pathology are often missing48. For example, it is still
debatable why familial mutations in the widely expres­
sed cell-cycle negative regulator gene RB1 cause mostly
retinoblastoma, without affecting other tissues49.
With the accumulation of tissue-wide molecular pro-
files, several features of causal genes and susceptible tis-
sues became apparent (Fig. 2). Below we present cellular
expression-based mechanisms that are common among
monogenic diseases, regulatory and network-based
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Table 1 | Representative human tissue profiling resources

Database No. of tissues/ Profiling method Clinical Refs
samples/donors state
mRNA
GTEx 51 (+ 2 CL)/~11,500/~700 RNA-seq Normal 14

HPA  44/122/122 RNA-seq Normal 18

Protein
HPA  32/122/122 IHC Normal and 18

diseased
Human Proteome Map 30/85/3 Mass spectrometry Normal 155

Non-coding RNAs
TissueAtlas (microRNAs) 61/61/2 Microarray Normal 156

DASHR 86 (+ 51 PC, 48 CL)/> 800/NR Data integration Normal 157

FANTOM5 (microRNAs, lncRNAs, 400/150 (+ 570 PC, 250 CL)/3 Various Normal 33,158

promoters, enhancers)
Regulatory elements
GTEx (eQTLs) 48/~ 10,000/~ 600 eQTLs Normal 14

ENCODE and Roadmap >120/NR/hundreds ChIP-seq, DNase-seq, Normal 22,32

Epigenomics ATAC-seq, FAIRE-seq

3D Genome 109/113/NR Hi-C, ChIA-PET, Normal 122

Capture Hi-C, PL AC-seq

TiGER 30 tissues Data integration Normal 159

Single cells expression profiles

Human Cell Atlas 3/17/17 scRNA-seq Normal and 16

diseased
Single Cell Portal 68 studies scRNA-seq Normal and
diseased
ATAC-seq, assay for transposase-accessible chromatin using sequencing; ChIA-PET, chromatin interaction analysis by paired-end tag;
ChIP-seq, chromatin immunoprecipitation coupled to sequencing; CL , cell lines; DASHR , Database of Small Human non-coding
RNAs; DNase-seq, DNase I hypersensitive site sequencing; ENCODE, Encyclopedia of DNA Elements; eQTLs, expression quantitative
trait loci; FAIRE-seq, formaldehyde-assisted identification of regulatory elements; FANTOM5, Functional Annotation of the Mammalian
Genome; GTEx, Genotype–Tissue Expression; HPA , Human Protein Atlas; IHC, immunohistochemistry ; lncRNA , long non-coding
RNA ; NR , not reported; PC, primary cells; PL AC-seq, proximity ligation-assisted ChIP-seq; RNA-seq, RNA sequencing; scRNA-seq,
single-cell RNA sequencing; TiGER , Tissue-specific Gene Expression and Regulation.

Tissue-exclusive expression
When expression of a gene
exceeds a predefined cut-off in
a single tissue. This is in
contrast to tissue-selective
expression, which refers to
expression in a subset of
tissues (>1 tissue).
Preferential expression
When expression of a gene is
elevated in a certain tissue
relative to its expression in
other tissues.
mechanisms that are common among monogenic, poly-
genic and complex diseases, and non-cell-autonomous
mechanisms. These mechanisms, while presented sepa-
rately, are often interdependent and can serve as a starting
point for elucidating the tissue-selective pathogenesis.
Expression-based mechanisms
This class of mechanisms is typical of monogenic diseases
caused by aberrations in protein-coding genes (Fig. 2a).
Distinct expression in disease-related tissues. A simple
mechanism for tissue-specific susceptibility is the exclu-
sive expression of the causal gene in susceptible tissues.
For example, the caveolin 3 (CAV3) gene encoding the
muscle-specific form of the caveolin protein family is
expressed primarily in heart and skeletal muscle, and
consequently, when mutated, causes cardiomyopathies
and skeletal muscle disorders. Likewise, certain genes
causal for kidney diseases were shown, via scRNA-seq
of mouse kidney, to be expressed exclusively in the
disease-related region of the nephron50. However, most
causal genes do not show a tissue-exclusive expression
(Fig. 1b), making this compelling mechanism pertinent
to a small subset of diseases.
Tissue susceptibility could also result from preferential
expression of the causal gene, that is, its over­expression
relative to its levels in unaffected tissues51. Large-scale
analyses of hundreds of monogenic disease genes1,3
revealed that preferential expression of causal genes in
susceptible tissues was a significant trend that was robust
to expression normalization procedures, was not domi-
nated by a specific disease or tissue1, and was common in
about a third to half of the diseases explored2,3. For exam-
ple, in Duchenne and Becker muscular dystrophy, the
causal gene encodes dystrophin (DMD), which anchors
the extracellular matrix to the cytoskeleton, and the
preferential expression of DMD in muscle is consistent
with the importance of its function to muscle physiology.
Another example, revealed by scRNA-seq of the mouse
respiratory system, is of a rare cell type expressing high
levels of the CFTR gene that is causal for CF; depletion
of that cell type led to pulmonary CF phenotypes11,26.
Tissue-selective expression is also observed at the
isoform level. Tissue-specific transcript isoforms were
observed for about half of the expressed human genes,
with isoforms resulting mostly from alternative tran-
scription start and termination sites rather than alter-
native splicing52. Preferential expression of isoforms53

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Paralogue
A homologous gene present in
the same organism, typically
having redundant functionality.
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Table 2 | Databases associating between traits, genes and tissues
Database Traits
Online Mendelian Mendelian diseases
Inheritance in Man
NHGRI–EBI GWAS Complex diseases and traits
Catalogue
Human Phenotype Ontology Diseases
DisGeNET Diseases and traits
Disease Ontology Diseases
Orphanet Rare diseases
NHGRI–EBI GWAS, US National Human Genome Research Institute–European Bioinformatics Institute Catalogue of published
genome-wide association studies; SNP, single-nucleotide polymorphism.
and tissue-specific splicing patterns of causal genes and
risk alleles were also demonstrated, although their
physiological roles often remained unclear54,55.
Could tissue susceptibility also occur due to under-
expression of the causal gene? A study that focused
on the tumour suppressor breast cancer gene BRCA1,
which maintains genome stability, showed that haplo­
insufficiency for BRCA1 led to cell type-specific
genomic instability and premature senescence, parti­
cularly in human mammary epithelial cells56. On a larger
scale, analysis of 51 cancer-initiating genes that are
causal for heritable cancer syndromes revealed that
loss-of-function cancer genes were under-expressed
in susceptible tissues, whereas gain-of-function cancer
genes were overexpressed (although some challenges
with the robustness of the computational approach
were indicated)1. This analysis suggests that, in loss-of-
function cancer aberrations, the protective function
of the compromised under-expressed gene becomes
insufficient. In gain-of-function cancer aberrations,
the enhanced malfunction of the aberrant gene product
is toxic. The latter effect was also observed in multiple
protein-misfolding diseases, such as synucleinopathies,
where aggregates containing the α-synuclein protein
accumulate in neurons or glial cells8.
Tissue-specific post-transcriptional processes. Gene
products typically undergo various types of post-
transcriptional processing that can affect their half-
life and function, making the relationship between
transcript levels, protein levels and protein activity
quite complicated and gene specific57. By affecting
the final gene products, post-transcriptional process-
ing that occurs in a tissue-specific manner can lead
to tissue-specific impact. One example is the post-
transcriptional process of nonsense-mediated decay
(NMD), which is responsible for eliminating mRNA
transcripts that contain premature stop codons.
NMD was shown to exhibit some tissue specificity,
which could in turn affect clinical manifestation in a
tissue-specific manner. For example, Schmid meta-
physeal chondrodysplasia is caused by heterozygous
mutations in the COL10A1 gene encoding collagen
X expressed in cartilage. In patients with premature
stop-codon mutations, mutant mRNAs were completely
Reviews
Association No. of associations Ref.
Disease, gene >7,000 diseases, 35
>3,900 genes
Trait, variant ~90,000 SNP–trait 160
associations
Phenotype, disease, >156,000 terms 36
tissue and gene annotated to diseases
Disease, gene >24,000 diseases, 161
>17,000 genes
Disease, tissue >9,000 terms associated 37
to clinical vocabularies
Disease, gene >6,000 diseases
degraded in cartilage but not in non-cartilage cells, lead-
ing to cartilage-specific collagen X haploinsufficiency58.
A large-scale study of protein-truncating mutants
estimated that 17% of the rare nonsense mutants pre-
dicted to trigger NMD have heterogeneous effects
across tissues59. Another example of a tissue-specific
post-transcriptional process is the bystander effect, a
phenomenon whereby a broadly expressed misfolded
protein overloads the proteostasis machinery, and thus
compromises the correct folding of unrelated meta­
stable proteins60. In Caenorhabditis elegans, for exam-
ple, the broadly expressed misfolded DAF-28 protein
led to neuron-specific dysfunction due to disrupting the
normal biogenesis of the unrelated endogenous DAF-7
protein; DAF-7 is expressed specifically in neurons and
its secretion is critical for proper developmental signal-
ling60. Due to their indirect nature, these downstream
processes are challenging to decipher.
Tissue-restricted functional redundancy. In the
aforementioned mechanisms, the causal genes had
tissue-specific properties, functions or impacts. Here,
in contrast, pathogenesis might emerge because of
limited expression of a different gene or entity, which
is functionally redundant with the causal gene and acts
as its backup. Accordingly, the backup masks the causal
aberration across unaffected tissues, but is insufficient
or absent specifically in susceptible tissues. One type of
backup is a paralogue (a homologue) of the causal gene.
Paralogous genes have been repeatedly shown to have
redundant functionality and to compensate for the loss
of each other in multiple species61–64 (reviewed in ref.65),
and dosage sharing between paralogues is suggested to
be one of the first steps following gene duplication66.
In several cases, backup by paralogues has been shown
to be dosage dependent67,68. For example, the essenti-
ality of the paralogous human helicases DDX3Y and
DDX3X increased when the expression level of the other
paralogue decreased, and vice versa64.
The role of paralogues of causal genes was recently
tested in a systematic manner across 112 tissue-specific
hereditary diseases2. In 43% of the cases, paralogues
were shown to be under-expressed relative to the causal
gene specifically in the susceptible tissue. Their lower
expression suggested that their backup capability was
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Mechanism Affected tissue
a Expression-based mechanisms
1 Exclusive expression
2 Preferential expression
3 Post-transcriptional
processes
4 Reduced functional
redundancy
F1
b Regulatory mechanisms
1 Disrupted regulatory
elements
2 Effects of eQTLs
3 Disrupted chromatin
contacts
c Tissue-disrupted networks
1 Disrupted molecular
interactions
2 Disrupted pathway
3 Disrupted gene-
module integrity
d Non-cell-autonomous mechanisms
1 Responsiveness to
signals
Unaffected tissue Fig. 2 | Illustration of the different mechanisms under­
lying tissue-selective manifestation of heritable traits
and diseases. Each row of the figure corresponds to a
mechanism and portrays its unique impact in the affected
tissue versus unaffected tissues. Although each mechanism
is portrayed separately for clarity , they are often inter­
dependent. Below we use ‘trait genes’ (marked red) to
refer collectively to disease-causing genes and risk alleles.
a | Mechanisms pertaining to the relative abundance of
trait genes. Exclusive or preferential expression of the trait
gene in the susceptible tissue (rows 1,2). Distinct post-
transcriptional processing of trait genes in the susceptible
tissue, such as enhanced nonsense-mediated decay (scis-
sors) of the trait gene’s transcript (row 3). A compensatory
factor (pentagon) that is functionally redundant with the
trait gene, is downregulated particularly in the susceptible
tissue (dashed lines), and thus unable to provide sufficient
F2 F3 F4 F5 F1 F2 F3 F4 F5 compensation. F1 to F5 correspond to the functions of the
trait gene and its compensatory factor, with functions F2 to
F4 being common to both (row 4). b | Mechanisms pertaining
to regulatory elements. Disruption of regulatory sites
accessible specifically in susceptible tissues, such as a
genomic region (red line) free of nucleosomes (row 1).
Disruption of expression quantitative trait loci (eQTLs) that
act specifically in the susceptible tissue. This subclass of
genomic regulatory elements (red rectangle) affects the
expression levels of target genes (red arrow), located in cis
or in trans to the eQTL, in a tissue-dependent manner (row 2).
Disruption of chromatin contacts (red region) alters the
spatial organization of genomic regions, thereby affecting
tissue-specific enhancer–promoter interactions (row 3).
c | Tissue-disrupted networks. Disruption of molecular
interactions of trait genes that occur exclusively in the
susceptible tissue will impact that tissue alone (row 1).
Disruption of a tissue-specific pathway , denoted as series
of arrows, that involves the trait gene. The pathway con-
verges specifically in the susceptible tissue and is not
active in unaffected tissues (row 2). Disruption of gene
modules (red shaded regions). The module that contains
known trait genes and suspected trait genes (pale-coloured)
is formed specifically in the susceptible tissue and not
in unaffected tissues (row 3). d | Non-cell-autonomous
mechanisms. The susceptible tissue exclusively responds
to a ubiquitous signal (grey circles) via a tissue-specific
receptor, and thus disruption of this response will impact
this tissue alone (row 1). The susceptible tissue responds via
a ubiquitous receptor to a signal that occurs exclusively in
its microenvironment (row 2).

treatment works by manipulating the splicing of its

2 Microenvironment paralogous gene, SMN2, to encode an otherwise lowly
expressed SMN2 isoform that is similar to the wild-type
SMN1 (refs77,78).

compromised in the susceptible tissue, thereby making
that tissue more sensitive to the effects of the aberration2.
Additional functional redundancies, such as alternative
metabolic pathways69, common regulation by distinct
transcription factors (TFs) 70, higher-order genetic
interactions71,72 and nonsense-induced transcriptional
compensation73,74, are yet to be examined as disease
modifiers in a large scale. Notably, backup mecha­
nisms are already of therapeutic interest75,76. For exam-
ple, spinal mus­cular atrophy is caused by aberration
in the SMN1 gene. Its antisense oligonucleotide-based
Regulatory mechanisms
This class of mechanisms pertains to aberrations in
genomic regions containing regulatory elements.
Such aberrations are typical of complex diseases and
traits mapped via GWAS, and often correspond to
non-coding, small-effect risk alleles79. Although the
functional consequence of many risk alleles remains
obscure, several tissue-selectivity mechanisms were
demonstrated across traits (Fig.  2b) . Below, we dis-
cuss regulatory mechanisms ranging from local and
small-scale effects on proximal genes to remote effects
across larger chromosomal scales.

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Expression quantitative
trait loci
(eQTLs). Genomic regions
containing DNA sequence
variants that influence the
mRNA expression level
of a gene.
NaTure RevIewS | GeNeTICs
Disruption of gene-specific regulatory elements.
Gene-specific regulatory elements have been repeat-
edly shown to function in a tissue-selective manner. For
example, transcriptional regulatory interactions were
shown to be more tissue specific than expected by the
expression of the TFs and target genes themselves51. The
disruption of gene-specific regulatory elements could
therefore elicit tissue-specific phenotypes, as thoroughly
demonstrated by the case of the obesity-associated locus
FTO. Analysis of the chromatin state of FTO across 127
human cell types revealed that it harbours an enhancer
that is specific to pre-adipocyte cells80. Further analysis
revealed that the FTO risk allele disrupts a conserved
repressor motif, thereby leading to de-repression of its
target genes, and consequently to a developmental shift
towards pro-obesity80.
Systemic cross-trait studies of the relationships
between gene-specific regulatory elements and non-
coding risk alleles showed that non-coding risk alleles
tend to be enriched in regulatory regions that were
active in trait-susceptible tissues81,82. For example, single-
nucleotide polymorphisms (SNPs) associated with
plasma low-density lipoprotein concentration over-
lapped significantly with peaks of the activation marker
H3K4me3 in liver83, and SNPs associated with type 2
diabetes mellitus and related traits were enriched speci­
fically in enhancers detected in pancreatic islets84.
Subsequently, enrichment of trait-associated SNPs
within active regulatory regions became a hallmark of
pathogenic tissues and was utilized to illuminate patho-
genic cell types81. Yet, the relationship between risk alleles
and active regulatory elements is not straightforward.
A study of tissue-specific regulation inferred by inte-
grating data of active chromatin noted only modest
enrichment of SNPs associated with Crohn’s disease,
rheumatoid arthritis and schizophrenia within tissue-
specific versus broadly active regulatory elements, sugges­
ting that additional genes expressed in disease-relevant
cells might impact pathogenecity82.
Effects of eQTLs. Expression quantitative trait loci (eQTLs)
are a class of non-coding regulatory elements whose poly­
morphism correlates with variation in the expression
levels of one or more genes85. eQTLs can reside in cis or in
trans with their target genes, and lead to their upregulation
or downregulation in a tissue-dependent manner. Owing
to the massive genome and transcriptome sequencing
carried by the GTEx consortium, thousands of eQTLs
were identified across tissues14. Tissue eQTLs were tested
for association with complex traits by calculating their
colocalization with risk alleles for traits that manifest in
the same tissues24,45. For example, a systematic study of
complex traits and diseases, including metabolic, cardio-
vascular, anthropometric, autoimmune and neurodegen-
erative traits, showed that eQTLs identified in susceptible
tissues were significantly enriched for trait-associated
SNPs45. This suggested that trait-associated SNPs act
by altering gene regulation in trait-related tissues.
However, as mentioned for the preceding mechanism,
in most traits, enriched eQTLs were generally tissue
shared and not tissue specific45, again suggesting the
involvement of additional genes and/or mechanisms.
Reviews
Disruptions of chromatin contacts. Application of chromo­
some conformation capture techniques revealed that
the human genome is partitioned into megabase-scale
topologically associated domains (TADs)86,87 that can
bridge the distances between enhancers and promot-
ers and thus affect gene regulation. Genetic aberrations
that disrupt TADs were shown to rewire enhancer–
promoter interactions and lead to the misexpression of
genes, resulting in pathogenic phenotypes such as limb
malformations88. Whereas many TADs were shown to
be highly conserved across tissues, a subclass of fre-
quently interacting regions showed strong tissue speci-
ficity in local chromatin interactions and was found near
tissue-specific genes23. The tissue-aware consideration of
TAD structures, their boundaries and their position rela­
tive to genes and enhancers could therefore illuminate
the tissue-specific pathogenicity of genetic aberrations89.
Tissue-disrupted networks
The mechanisms below refer to alterations in the molecu­
lar interaction patterns of single genes or gene subsets,
which are relevant to both monogenic and polygenic
diseases (Fig. 2c).
Disrupted tissue-specific molecular interactions. Widely
expressed proteins can carry different functions across
tissues by interacting with distinct molecules per tis-
sue90, allowing a ubiquitous aberration to manifest as a
tissue-specific phenotype. For instance, the gene dystro-
glycan 1 (DAG1), which is causal for muscular dystrophy–
dystroglycanopathy, encodes a globally expressed cell
adhesion receptor. Specifically in muscle, DAG1 forms
the dystrophin–glycoprotein complex by interacting
with DMD91 and CAV3 (ref.92) proteins, which are expres­
sed primarily in muscle, thereby explaining its muscle-
specific pathology. A systematic analysis of over 300
diseases showed that, like DAG1, causal genes tend to
form tissue-specific protein–protein interactions (PPIs)
preferentially in susceptible versus unaffected tissues3.
Do disease-causing mutations in such genes indeed
affect PPIs? A large-scale yeast two-hybrid analysis of
220 causal genes revealed that 61% of the disease-causing
alleles exhibited partial loss of their wild-type PPIs93
(denoted edgetic perturbation) 94. Taken together,
these studies suggest that disease-causing mutations
could perturb PPIs that are specific to the susceptible
tissue, thereby contributing to tissue-specific disease
manifestation3.
Disrupted tissue-specific pathways and gene modules.
Pathways are biological processes performed by sub-
sets of gene products and other molecules, and may
involve metabolic reactions, as in glycolysis, or regula-
tory and protein interactions, as in signalling cascades.
The activity of pathways varies across tissues, with some
pathways being highly tissue specific and thus causing
tissue-specific pathologies when disrupted. For instance,
the glycogenolysis pathway, whereby the polysaccha-
ride glycogen is degraded, takes place mainly in liver
and muscle, and thus glycogen storage diseases95, which
are caused by aberrations in glycogenolysis enzymes,
manifest primarily in those tissues.
volume 21 | March 2020 | 143
Reviews
Whereas pathways can be delineated, gene modules
are defined more loosely as subsets of functionally
related genes that tend to be co-expressed, encode
products that physically interact with each other, or lead
to similar phenotypes when individually perturbed96.
The concept of gene modules can be extended to that
of disease modules, which comprise genes associated
with a certain disease28,97. The incorporation of addi-
tional functionally related genes into disease modules
could illuminate disease mechanisms. For example,
a disease module of asthma that incorporated the
local interactome neighbourhood of known asthma
genes was enriched for genes with modest P values
in an asthma GWAS, and for genes that were differ-
entially expressed in response to treatment with an
asthma-specific drug27.
Similarly to pathways, modules may be estab-
lished in a tissue-dependent manner47,98. A study of
37 GWAS traits showed that risk alleles often perturb
regulatory gene modules that were highly specific to
disease-relevant tissues47. Another study of disease
modules for 70 tissue-specific polygenic diseases,
which determined module connectivity per tissue by
the interactome connectivity between the genes pref-
erentially expressed in that tissue, showed that disease
module connectivity was significantly high particularly
in disease-related tissues98. These studies suggest that
the integrity of a disease module is important for its
tissue-specific functionality and that aberrations that
compromise this integrity could lead to tissue-specific
pathologies.
Non-cell-autonomous mechanisms
The mechanisms below involve inter-cellular inter­
actions and pertain to monogenic and polygenic diseases
(Fig. 2d).
Tissue-specific responsiveness to signals. Tissue-specific
proteins tend to be enriched for proteins function-
ing as receptors99, indicating that one determinant of
tissue-specific functions is the variance in the respon-
siveness of tissues to signals. The impact of such signals
on disease predisposition was recently demonstrated for
breast and ovarian cancers caused by familial mutations
in BRCA1 (ref.100). Breast and ovaries are the primary
tissues that express the oestrogen receptor and thus
respond to oestrogen. A study showed that oestrogen
signalling induces DNA double-strand breaks in breast
cancer cells and epithelial cells of mouse mammary
glands, leading to pathological topoisomerase II–DNA
complexes; these pathological complexes are eliminated
by the normal function of BRCA1, yet accumulate when
BRCA1 is depleted100. This mechanism demonstrates
how tissue-specific pathogenesis can emerge, despite
both the signal and the disease-causing gene being
widely expressed.
Tissue-specific microenvironment. Cells continuously
interact with their microenvironment by cell–cell phys-
ical contacts and by processing chemical signals in the
form of diffusible molecules. Blood-transferred mole-
cules and infiltrating immune cells tend to be shared
144 | March 2020 | volume 21 www.nature.com/nrg
across tissues; however, certain tissues maintain their
own unique environment via a functional barrier that
separates them from the blood, such as the blood–brain
and blood–testis barriers. The importance of the tissue
microenvironment in general, and of tissue barriers in
particular, is revealed by diseases that are associated with
barrier leakage. For example, blood–brain barrier leak-
age was observed in patients with Alzheimer disease101
and disruption of the blood–testis barrier was associated
with male infertility102.
Notably, the tissue microenvironment is also critical
for therapy. For example, the Gaucher lysosomal storage
disorder results from mutations in the glucocerebrosi­
dase enzyme that catalyses the breakdown of gluco­
cerebroside, which consequently builds up in lysosomes.
Gaucher types differ in the tissues they affect: Gaucher
type 1 (where brain is spared) and the non-neurological
symptoms of Gaucher type 3 are treated with enzyme
replacement therapy; this treatment cannot be applied
to the neurological symptoms of Gaucher type 3 due to
the blood–brain barrier.
The fate and function of immune cells are parti­
cularly affected by the tissue microenvironment103.
Memory T cells, for example, which are central players
in the adaptive immune response, were shown to
acquire distinct phenotypes, depending on tissue-
specific environmental cues104. Likewise, tissue-resident
macro­phages present tissue-specific functional charac­
teristics105, such as their capability for clearing mutant
cells 106. The impact of the microenvironment on
the emergence of autoimmune disorders is demon-
strated by coeliac disease, which manifests in the
small intestine upon exposure to gluten protein pre­
sent in grains. Coeliac disease tends to be inherited in
families harbouring a specific isoform of the HLA-DQ
protein that is part of a major histocompati­bility
complex (MHC) class II antigen-presenting cell
receptor. The isoform-bearing receptor has higher
affinity to gluten-related peptides, the exposure to
which is limited to the gastrointestinal tract, thereby
contributing to the activation of a tissue-specific
autoimmune process.
Further understanding tissue-specific mechanisms
Many more mechanisms that underlie tissue selec-
tivity await discovery. Mechanisms involving post-
transcriptional modifications as well as mechanisms that
pertain to the cellular composition and spatial organiza-
tion of each tissue have typically remained hidden since
molecular profiling has been mostly applied to trans­
criptomes, and particularly to transcriptomes of bulk tis-
sues or cell populations. Additionally, broad surveys of
tissue expression across many tissues have largely been
done on unaffected individuals, most of which were
adults, and thus do not reflect the impact of germline
aberrations on unaffected tissues nor reveal expression
patterns in early developmental stages and childhood.
Inclusion of emerging types of data, such as single-cell
measurements, proteomics and spatiotemporal profiles,
as well as broad surveys of developmental stages107 and of
disease states across affected and unaffected tissues108,109,
will refine current observations and unravel additional
 Reviews

molecular mechanisms underlying tissue-selective
susceptibility.
Exploring tissue-selective mechanisms
The identification of the molecular mechanism under­
lying disease manifestation is a huge challenge that often
remains unmet even for well-studied diseases. Yet, by
focusing on the narrower question of illuminating
the molecular basis of their tissue selectivity, we may
obtain important insight that could enhance the search
for treatment80,110. This narrower question can now be
approached owing to the tremendous amounts of molec-
ular data of diseases and tissues that have become avail­
able for exploration. Below, we point to publicly avail­able
large-scale databases and web tools that allow non-
computational investigators to harness this extensive
information towards a better under­standing of the
mechanisms underlying the tissue selectivity of their
disease of interest. These resources have also been
of great importance to computational researchers
and enabled many of the studies cited herein. The tools
and strategies that we describe are exploratory; they can
serve to refute candidate mechanisms and to support
or speed the detection of potentially relevant mecha-
nisms. As with other exploratory investigations, poten-
tial mecha­nisms should be scrutinized via literature
mining and verified experimentally. We open this sec-
tion with tools that can be used to associate a disease
or trait of interest with its causal genes, risk alleles and
affected tissues. We then describe tools for the explor-
atory analysis of potential mechanisms pertaining to
protein-coding and non-coding disease genes and
risk alleles (Fig. 3). We end with a short description of
experimental strategies.
Connecting traits and diseases to genetic factors and
susceptible tissues
Given a heritable disease or trait, this step aims to gather
available information on their known causal genes and
risk alleles as well as the tissues and cell types in which
they manifest, thereby providing the foundation for
studying their tissue selectivity (Table 2). Investigations of

Tissue-selective Experimental models

trait/disease
Cell line
TissueNet (cellular focus)
GIANT
GTEx DifferentialNet Reactome
OMIM HumanBase
NHGRI–EBI GWAS HPA
HPO/DO Network
Orphanet Expression Pathways and
modules Organoid
(tissue focus)
Coding

Non-coding
Animal model
Regulatory Chromatin (in vivo/inter-tissue focus)
elements contact maps
eQTLs
ENCODE 3D Genome
Roadmap Epigenomics GTEx
FANTOM5
IHEC

Fig. 3 | A schematic flow chart illuminating tissue-selectivity mechanisms. The analysis starts with a tissue-selective
trait or disease (left). The underlying genetic factors can be extracted from Online Mendelian Inheritance in Man (OMIM)
and the US National Human Genome Research Institute–European Bioinformatics Institute Catalogue of published
genome-wide association studies (NHGRI–EBI GWAS). Additionally , affected tissues can be deduced from Human
Phenotype Ontology (HPO), Disease Ontology (DO) and Orphanet. The analysis continues with exploration of potential
mechanisms that might explain the tissue-selective disease manifestation, by using tissue-aware resources and tools
(middle). Mechanisms pertaining to protein-coding genes (upper part) include expression-based mechanisms, which can
be explored via resources such as the Genotype–Tissue Expression (GTEx) and the Human Protein Atlas (HPA) portals;
interaction-based mechanisms, which can be evaluated via tools such as TissueNet, Genome-wide Integrated Analysis of
gene Networks in Tissues (GIANT), and DifferentialNet; and pathway-based and module-based mechanisms, which can be
inferred from resources such as Reactome and HumanBase. Mechanisms pertaining to non-coding variations (lower part)
include aberrant tissue-specific regulatory elements, which can be deduced from resources such as the Encyclopedia of
DNA Elements (ENCODE); aberrant tissue expression quantitative trait loci (eQTLs), available through GTEx; and aberrant
chromatin contacts, available via, for example, 3D Genome. Additional mechanisms, tools and resources are mentioned
in the main text. The analysis concludes with experimental testing of putative mechanisms in tissue-aware modelling
systems (right). These include modelling systems aimed at testing cellular mechanisms such as tissue culture and cell lines,
modelling systems aimed at testing intra-tissue mechanisms such as organoids, or modelling systems aimed at testing
in vivo, inter-tissue mechanisms such as model organisms. FANTOM5, Functional Annotation of the Mammalian Genome;
IHEC, International Human Epigenome Consortium.

NaTure RevIewS | GeNeTICs volume 21 | March 2020 | 145

Reviews
Mendelian diseases typically start with querying the estab-
lished and manually curated OMIM database35. OMIM
points to the genetic factors that are known or suspected
to cause Mendelian diseases, along with richly curated
phenotypic, molecular and clinical data. Investigations of
risk alleles for complex diseases and traits can addition-
ally query the US National Human Genome Research
Institute–European Bioinformatics Institute (NHGRI–
EBI) GWAS Catalogue111. To associate a disease or trait
of interest with its clinical manifestation, including its
susceptible tissues, pathology-oriented ontology data-
bases come to aid. HPO36 and Disease Ontology37 cover
hundreds of diseases. HPO can be queried by dis-
ease and/or phenotype to obtain its associated genes,
affected anatomical systems and related diseases, which
can be explored in a hierarchical manner (for exam-
ple, moving from kidney abnormality to renal mor-
phology). Orphanet, an online database dedicated to
rare diseases, also presents phenotypic abnormalities
by the frequency of their occurrence in patients, and
thus could also illuminate causative versus secondary
phenotypes and tissues112.
Exploring expression-based mechanisms
Although the fraction of tissue-exclusive and pref-
erentially expressed genes is not high (Fig. 1b,c), it is
worthwhile to check the expression patterns of causal
genes in susceptible versus unaffected tissues, as a
clear differential expression could immediately indi-
cate a causal mechanism1,3. Several resources enable
the rigorous examination of the expression patterns
of genes across tissues (Table 1). GTEx and HPA offer
user-friendly views of the expression of wild-type genes
across tissues and are based on analysis of hundreds
and tens of donors, respectively. GTEx additionally
supports gender-based views and enables analysis of
tissue-specific splicing by presenting the expression lev-
els of exons, exon junctions and isoforms per gene across
tissues (note that only reads that mapped to known
exons are considered, leaving new exons undetected).
HPA additionally annotates genes as preferentially
expressed and portrays protein expression levels across
tissues. Despite GTEx and HPA datasets not contain-
ing overt information on post-transcriptional changes
and focusing on samples from adults, their ease of use
makes them a focal point for querying the expression
patterns of causal genes, risk alleles and other factors.
Data of gene expression patterns at the cell-type level
are also emerging via single-cell resources, such as the
Human Cell Atlas16, and are already viewable via mouse
cell atlases113–115.
Notably, expression resources might also illumi-
nate pathogenic versus affected tissues and cell subsets,
such as when the causative cells or tissues express the
causal gene but the affected cells or tissues do not, as
demonstrated for kidney diseases43. Likewise, alongside
exploring the expression patterns of causative genes and
risk alleles, these resources can be used to explore the
expression patterns of functionally related genes that
might impact disease manifestation in a tissue-specific
manner, such as molecular interactors (for example,
kinases), modifier genes (such as a paralogue), relevant
146 | March 2020 | volume 21 www.nature.com/nrg
pathway or module genes, or upstream receptors.
Additional tissue expression resources appear in Table 1.
Exploring tissue-specific regulatory mechanisms
Multiple non-coding variants and risk alleles, which
are often identified in GWAS, lead to phenotypes by
affecting gene regulation. However, the interpretation
of these variants is typically more complex than that of
protein-coding genes and multiple approaches with vary-
ing levels of complexity have been devised to address this
challenge24,116–119. Here, we focus on web tools and portals
that are amenable to exploration by non-computational
researchers. In general, these resources offer detailed
views into the epigenome of multiple tissues and cell
types, and include multiple histone marks (methylation
and acetylation at various sites), DNase I hypersensitiv-
ity sites, TF binding sites, DNA methylation, predicted
microRNA sites, enhancers, chromatin contacts, and
more, which were mapped by ENCODE, Roadmap
Epigenomics32, FANTOM5 and other projects23 (Table 1).
Besides portals dedicated to these projects, data can
be accessed via epigenome-specific data portals such
as the International Human Epigenome Consortium
(IHEC) portal120.
A typical workflow with these tools is to select the
epigenetic marks and the samples for analysis and view
them while focusing on the query region. Viewing is
enabled via dedicated regulation tracks in browsers
such as the UCSC genome browser and the WashU epi­
genome browser. The genetic variation track that con-
tains common and pathological variations could further
illuminate the likely impact of variants of interest in the
query region. The involvement of a query variant in
long-range chromatin interactions within tissues can
be observed via additional browsers121, such as the 3D
Genome Browser122. The tools described above are not
quantitative or probabilistic and thus are more suitable
for qualitative analysis.
Examples of web tools offering probabilistic analy-
ses include FORGE, which identifies cell type-specific
enrichments of query variants in DNase I hypersen-
sitivity sites123, and eFORGE, which identifies cell
type-specific regulatory signals in a set of differentially
methylated positions identified in epigenome-wide asso-
ciation studies117. The involvement of a query variant in
tissue-specific eQTLs and splice QTLs can be assessed
via the GTEx portal, which calculates the likelihood
per query.
Although each specialized tool may seem detached,
the combination of epigenome datasets that can identify
regulatory elements active in given tissues, expression
datasets that can show which transcripts are expressed
in a given tissue, and chromatin contact maps that link
potential enhancers and promoters, could provide a big
leap forward in interpreting tissue genotype–phenotype
relationships80,124.
Exploring network-based mechanisms
Functional understanding of the tissue-specific impact
of variation on protein functions can be gained by
exploring the physical interactions and functional rela-
tionships among proteins in tissue contexts and by using

tissue-aware tools for the exploration of pathways and
network modules.
Tools for exploring molecular relationships in tissue
contexts. The tissue-specific impact of a ubiquitously
expressed disease gene could be mediated by the tissue
specificity of its molecular interactions. How extensive
is our knowledge of such interactions? Transcriptional
regulatory interactions have been mapped across tissues
and cell lines for several TFs32,33. PPIs, by contrast, despite
them being extensively mapped (over 380,000 PPIs
involving ~20,000 proteins have been detected experi-
mentally), have often been measured in model systems
and thus lack tissue contexts. To partially close this gap,
tissue contexts for PPIs have been inferred from tissue
expression profiles. Accordingly, PPIs involving proteins
that were absent or lowly expressed in a given tissue were
disregarded or downplayed in that tissue125,126.
As tissue proteomic profiles were limited, the infer-
ence of tissue contexts for PPIs relied on tissue trans­
criptomes, under the assumption that transcript levels
correlate with protein abundance. This assumption has
been much debated, yet multiple studies found mode­
rate correlations at steady state19,127, especially when
gene-specific conversions from transcript to protein
levels were applied57. Attesting to the validity of this
gap-closing procedure, tissue molecular interaction
networks (interactomes) comprising transcription regu­
lation47,51, PPIs3,128 or functional relationships (also
including co-expression and other types of non-physical
relationships)31 were shown to be advantageous over
unfiltered interactomes in uncovering protein functions,
prioritizing disease genes or interpreting GWAS47,128.
Several tools enable the exploration of physical inter-
actions and other functional relationships for genes of
interest and their products (Table 3). Some tools addition-
ally highlight tissue-specific inter­actions, which could
be extremely useful for illuminating tissue-selectivity
mechanisms. These include TissueNet for PPIs129,
Genome-wide Integrated Analysis of gene Networks
in Tissues (GIANT) for functional relationships31, and
DifferentialNet for upregulated or downregulated PPIs130.
Tools for exploring the tissue activity of pathways and
gene modules. Tissue-specific pathogenesis might stem
from the involvement of causal genes and risk alleles
in pathways and gene modules that are specific to
Table 3 | Representative tissue-aware databases of molecular relationships
Database Details Ref.
TissueNet PPIs, highlights tissue-specific versus ubiquitous proteins
as well as differentially expressed proteins
DifferentialNet Differential PPIs, highlights causal genes
HIPPIE PPIs, confidence scored
HumanBase Functional interactions, confidence scored
SPECTRA PPIs, tissue and tumour networks
GNAT Co-expression relationships
Reactome Expression of pathway-associated proteins
GNAT, Genetic Network Analysis Tool; HIPPIE; Human Integrated Protein–Protein Interaction
Reference; PPI, protein–protein interaction; SPECTRA , SPECific Tissue/Tumour Related PPI
networks Analyser.
NaTure RevIewS | GeNeTICs
Reviews
susceptible tissues. The association of genes to known
pathways can be explored via the Reactome pathway
database131. Reactome records hundreds of curated
pathways and presents their activity across tissues
according to the tissue expression levels of pathway
genes (similar approaches to estimate the tissue activi-
ties of known cellular and metabolic pathways have been
used in multiple studies)132–134. Apart from exploring
tissue-specific pathways, the set of disease-associated
genes can also be compared against ubiquitous path-
ways that might be upregulated in the susceptible tis-
sue. For example, a recent analysis of PD-associated
genes revealed that they were significantly enriched
in a lysosomal gene set that was highly expressed in
astrocytic, microglial and oligodendrocytic subtypes,
suggesting that PD risk is associated with a perturba-
tion of a ubiquitous cellular process affecting a range of
cellular subtypes9.
In addition to exploring known pathways, one can
explore whether disease-associated genes constitute a
gene module within the interactome of the suscepti-
ble tissue. This analysis is available via HumanBase9,
which also offers tools that use tissue interactomes for
interpreting GWAS31. Given that a recent study found
that common genetic variation affects both overall
risk and clinical presentation of severe neurodevelop-
mental brain disorders that were likely to be mono-
genic135, network-based approaches could be harnessed
to illuminate the contribution of common alleles in
a tissue.
Notes on experimental model systems
Experimental assessment of candidate tissue-specific
mechanisms is a complex task. Part of the challenge is
specific to the traits and mechanisms in question such
as defining an indicative phenotypic readout and assess-
ing the potentially minor effect of a single mechanism.
A more general aspect of the complexity relates to the
experimental system representing the different types
of tissues. Cell lines in culture are the simplest models;
however, they do not fully recapitulate the physiology of
intact tissues in vivo and certainly not inter-tissue com-
munication. By contrast, in vivo models are typically
challenging, expensive and time consuming.
A model system that has arisen in recent years is
induced pluripotent stem cells that are subsequently dif-
ferentiated into cell types of interest136. Patient-derived
cells can be used to model tissues that might be inacces-
sible or challenging to grow such as neurons. Moreover,
they can be genetically manipulated, such that isogenic
pairs with and without a relevant mutation can be created
129
and differentiated into distinct cell types. The cell types
that are functionally affected by the mutation relative to
130
the non-mutant cells can then be revealed. The mode
162
of action of the mutation could be tested, for example,
31
by comparing the expression profiles of these otherwise
163 genetically identical cells or by comparing the interaction
164 profiles of the wild-type and mutant gene products.
As an alternative approach, organoids provide a
131
system that encompasses multiple cell types and their
interactions but without much of the organismal com-
plexity or time delays of full in vivo models137. Similarly
volume 21 | March 2020 | 147
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to haematopoietic transplants, organoids can be crea­
ted with mixed genotypes and utilized to assess the
effect of mutant cells on other, non-mutant cell types.
Additionally, the emerging technique of cell-lineage
tracking can be used to track developmental disorders,
thereby unravelling the stages and cell types in which
the mutation has a functional effect 138. Combined
with the huge progress in genetic editing of model sys-
tems and organisms, recently enhanced with tools for
efficient polygene editing139, these technologies pave
the way for easier modelling and, ultimately, a better
understanding of disease aetiologies.
Conclusions and future perspectives
Tissue selectivity of traits and diseases is a widespread
phenomenon that encompasses hundreds of heritable
monogenic and polygenic diseases and traits (Fig. 1).
It is also relevant for somatic genetic diseases, including
cancers, as many cancer-driver genes are ubiquitously
expressed and yet the cancers they elicit are enigmat-
ically tissue selective140 (Box 1). The understanding of
the pathophysiological mechanisms that render certain
tissues susceptible to genetic perturbation while
other tissues remain robust is important, not only for
genetically solved diseases, but also for unsolved dis-
eases. The tendency of disease genes to be preferen-
tially expressed and functionally related to each other
in affected tissues, or to colocalize with tissue eQTLs,
was harnessed for the identification of causal fac-
tors31,116,118,141, and simi­lar approaches helped illuminate
affected tissues and cell types38,142. These pathophysio-
logical mechanisms could also be employed for develop-
ing tissue-selective treatments as demonstrated for the
calcium-sensing receptor143.
We described multiple types of mechanisms that
underlie tissue selectivity (Fig. 2), yet many important
mechanisms await characterization, such as develop-
mental mechanisms124, secondary modifier genes144,
and the impact of common variants135 and environmen-
tal factors145. Whereas some mechanisms were exposed
owing to disease-directed efforts, as in the case of
BRCA1 (ref.100), other mechanisms were revealed owing
to recent advancements in high-throughput omics tech-
niques, as in the case of CF11,26, and the emergence of
publicly available online tools and resources presenting
heterogeneous omics datasets, as in the cases of FTO80
and ICR124 (Fig. 3). Continued technological progress and
reduction in costs are likely to expand the array of omics
techniques towards interrogating the meta­bolome, pro-
teome146, microbiome, inter-cellular communication
networks29,147,148 and other ‘–omes’ across a variety of
physiological systems and diversified groups of cohorts.
Largely owing to the huge amount of data they hold,
omics resources are sometimes perceived as overwhelm-
ing and are consequently used only for preliminary
qualitative analyses. Sophisticated analytical tools and
statistical methods continuously improve; however,
many of them are employed only by computational
experts. Given the large numbers of traits and diseases
awaiting resolution and the critical needs of patients,
more efforts should be invested in making these power­
ful tools and resources accessible and comprehensible
to a wider community of non-computational researchers
and clinicians. Together with investing in holistic studies
of ubiquitously expressed disease genes that may lead to
tissue-specific gene-dependent and variant-dependent
phenotypes, these efforts will facilitate the discovery of
pathophysiological mechanisms and consequently con-
tribute to better diagnosis, understanding and treatment
of traits and diseases.
Published online 8 January 2020

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Acknowledgements
We thank A. Rudich, V. Chalifa-Caspi, A. Monsonego and
members of the Yeger-Lotem lab for their helpful comments.
Author contributions
Both authors contributed to all aspects of the article.
Competing interests
The authors declare no competing interests.
Peer review information
Nature Reviews Genetics thanks M. Kuijjer and the other,
anonymous, reviewer(s) for their contribution to the peer
review of this work.
Publisher’s note
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claims in published maps and institutional affiliations.
Supplementary information
Supplementary information is available for this paper at
https://doi.org/10.1038/s41576-019-0200-9.
Related links
3D Genome: http://promoter.bx.psu.edu/hi-c/index.html
Database of small Human Non-coding RNAs (DAsHR):
http://dashr2.lisanwanglab.org/index.php
DifferentialNet: http://netbio.bgu.ac.il/diffnet/
Disease Ontology: http://disease-ontology.org/
DisGeNeT: http://www.disgenet.org/
encyclopedia of DNA elements (eNCODe):
https://www.encodeproject.org/
Functional Annotation of the Mammalian Genome
(FANTOM5): http://fantom.gsc.riken.jp/5/
Genetic Network Analysis Tool (GNAT):
http://mostafavilab.stat.ubc.ca/gnat/#
Genotype-Tissue expression (GTex):
https://gtexportal.org/home/
HiPPie: http://cbdm-01.zdv.uni-mainz.de/~mschaefer/hippie/
Human Cell Atlas: https://www.humancellatlas.org/
Human Phenotype Ontology (HPO): https://hpo.jax.org/app/
Human Protein Atlas (HPA): https://www.proteinatlas.org/
Human Proteome Map:
http://www.humanproteomemap.org/index.php
HumanBase: https://hb.flatironinstitute.org/
Us National Human Genome Research institute–european
Bioinformatics institute (NHGRi–eBi) GwAs Catalogue:
https://www.ebi.ac.uk/gwas/
Online Mendelian inheritance in Man (OMiM):
https://www.omim.org/
Orphanet: https://www.orpha.net/
Reactome: https://reactome.org/
Roadmap epigenomics Project:
http://www.roadmapepigenomics.org/
single Cell portal: https://portals.broadinstitute.org/single_cell
sPeCific Tissue/Tumour Related PPi networks Analyser
(sPeCTRA): https://alpha.dmi.unict.it/spectra/
TissueAtlas: https://ccb-web.cs.uni-saarland.de/tissueatlas/
TissueNet: http://netbio.bgu.ac.il/tissuenet/
Tissue-specific Gene expression and Regulation (TiGeR):
http://bioinfo.wilmer.jhu.edu/tiger/
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