HUMAN GENETICS

 Genetics (Greek genno = give birth) is the study of

variation of organisms, cause of variations (genes) and
transfer of these variation from parents to offsprings
(heredity)
 Word "genetics" was first suggested by British scientist
William Bateson in a personal letter to Adam Sedgwick,
dated April 18, 1905.
Science of variation and heredity in
human beings is “HUMAN GENETICS”
Print of the letter to
Alan Sedgwick .
Can you read it?
OBJECTIVES
 Different modes of inheritance
Autosomal and sex linked
Dominant and recessive
Mitochondrial inheritence
 Inborn errors
 Linkage analysis
 Pedigree analysis
 Linkage disequilibrium Analysis
 Structure and function of human genome

LINE, SINE, CpG islands, satellites, Mini and Microsatellites, Major human gene families
OBJECTIVES CONT…
 Chromosomal structure AND abnormalities
 Inversion deletions, translocations

 Point mutations

 Mechanisms of gene expression

 Oncogenes

 Gene therapy and Genetic counseling

 Molecular methods involved in study of Human

Genetics
RESOURCES
 Virtual Library on genetics
www.ornl.gov/sci/techresources
 Books in MMG and Main Library
 Introduction to Human Molecular Genetics;
Mechanisms of Inherited Diseases
http://site.ebrary.com/lib/punjab/Doc?id=10113938&ppg=1

 Books database at NCBI

 Google books 
  Nature reviews
www.nature.com
 BMC Genetics
www.biomedcentral.com
RESOURCES
 Human Genome Project
 www.genome.gov
 www.sanger.ac.uk/HGP
 "HUM-MOLGEN is a mailing list and literature resourcs
on HUMan MOLecular GENetics
 Human Genetics Commission (HGC)

www.hgc.gov.uk

 Genetics home reference

ghr.nlm.nih.gov
GENE
A gene is defined as: "a DNA segment
that contributes to
phenotype/function. In the absence
of demonstrated function a gene may
be characterized by sequence,
transcription or homology". 
 LOCUS AND ALLELE
locus is a point in the genome, identified by a marker, which can be mapped by some
means. It does not necessarily correspond to a gene; it could, for example, be an
anonymous non-coding DNA segment or a cytogenetic feature..
Null allele (amorph), Hypomorph, hypermorph, Neomorph, Antimorph

Alternative version of a gene that may occupy a given locus

MULTIPLE ALLELES
 The state of having more than two
alternative contrasting characters
controlled by multiple alleles at a single
genetic locus
 EXAMPLE
 Gene IA [protein A, on RBC membrane] is Dominant
 Gene IB [protein B on RBC membrane] is Dominant
 Gene i [absence of A & B protein on RBC membrane] is
Recessive to both A & B
 Blood Type A = genotype AA or Ai
 Blood Type AB = genotype AB
 Blood Type B = genotype BB or Bi
 Blood Type O = genotype ii
DOMINANCE, CODOMINANCE

 Both Alleles are completly Dominant Recessive

expressed Curled Up Nose Roman Nose

 Gene product is found for Can Roll Tongue Can't Roll

Tongue
both alleles
Widow's Peak No Widow's
Peak
Facial Dimples No Facial
Disease Gene is...
Dimples
Polydactylism dominant
Marfan syndrome dominant
Some types of Dwarfism recessive
Tay-Sachs disease recessive
 Penetrance
 complete penetrance
 incomplete penetrance

familial cancer syndromes (BRCA1 or BRCA2) gene

 Expressivity
For example, the features of Marfan syndrome vary
widely— some people have only mild symptoms (such as
being tall and thin with long, slender fingers), while
others also experience life-threatening complications
involving the heart and blood vessels. Although the
features are highly variable, most people with this
disorder have a mutation in the same gene (FBN1).
reduced penetrance and variable expressivity is probably
caused by a combination of genetic, environmental,
and lifestyle factors
 Allelicheterogeneity
A single disorder, trait, or pattern of traits caused
by different mutations within a gene

 Locus heterogeneity
A single disorder, trait, or pattern of traits caused
by mutations in genes at different chromosomal
loci
Allelic Heterogeneity
Mutations in RET (receptor tyrosine kinase) gene can cause

 Failure of development of colonic ganglia leading to defective

colonic motility (Hirsch-sprung disease)
 Inherited cancer of thyroid (multiple endocrine neoplasia type
IIa and IIb)
 Both
 Locus Heterogeneity
Retinitis pigmentosa
Autosomal dominant 12 loci
Autosomal recessive 8 loci
X-linked forms 24 loci

Ehlors-Danlos Syndrome Skin and underlying

tissue may be elastic and fragile because of
defect in collagen structure
(10 loci involved)
 Autosomal Dominant Huntington disease,
neurofibromatosis type 1
 Autosomal recessive.cystic fibrosis, sickle cell
anemia
 X-linked dominant.fragile X syndrome
 X-linked recessivehemophilia, Fabry disease
 Codominant alpha-1 antitrypsin deficiency
 Mitochondrial Inheritance (maternal
inheritance).Leber’s hereditary optic neuropathy
(LHON)
HUMAN GENE NOMENCLATURE
 In 1979 full guidelines for human gene nomenclature
were presented at the Edinburgh Human Genome
Meeting (HGM). 
 HUGO genome nomenclature committee (HGNC)
approves names and symbols of the genes.
 So far this committee has approved 23000 symbols.

 Guidelines on nomenclature are available on

http://www.gene.ucl.ac.uk/nomenclature/guidelines.html
SUMMARY OF THE GUIDELINES
 Each approved gene symbol must be unique.
 Symbols are short-form representations (or
abbreviations) of the descriptive gene name.
 Symbols should only contain Latin letters and Arabic
numerals.
 Symbols should not contain punctuation.
 Symbols should not contain "G" for gene.
 Symbols do not contain any reference to species, for
example "H/h" for human.
 GENE NAMES
 Names start with a lower case letter unless it is a person's name
describing a disease/phenotype or a capitalised abbreviation e.g.
AHDS "Allan-Herndon-Dudley syndrome" and ABCA1  "ATP-
binding cassette, sub-family A (ABC1), member 1", respectively
 Descriptive modifiers should follow the main part of the name,
separated by commas e.g. ACO1 "aconitase 1, soluble".
 Where a complete alternative name (or names) is being included as
part of the name, this should be in parentheses e.g. IDS "iduronate
2-sulfatase (Hunter syndrome)".

 Names of other species must be placed in parentheses at the end

e.g. LFNG  "lunatic fringe homolog (Drosophila)" and ANLN
"anillin, actin binding protein (scraps homolog, Drosophila)".
 If there is P at the end it describes Pseudogene
 For anonymous DNA sequences use D followed by 1-22, X or
Y to denote chromosome then s for unique segment, Z for
specific repetitive DNA family F for Multilocus DNA
family,and finally a serial number. E at the end shows that
sequence is known to be expressed.
 CRYBA 1- Gene for crystallin, beta A1 polypeptide

 AK2 – Gene for adenylate Kinase locus 2

 DXYS6X -DNA segment on X chromosome with a known homolog on Y and

representing 6th such homolog to be classified.
 D3S2550E- Unique DNA segment number 2550 on chromosome 3, expressed.
 D11Z3- Chromosome 11 specific DNA repetitive family number 3.

 FRA 16A- Fragile site A on chromosome number 16.

HUMAN GENETICS
METHODOLOGY
Lecture 2
 Pedigree Analysis
 Cytogenetics
 Karyotyping
 different banding patterns
 FISH
 SKY
 Gene mapping
 Somatic cells hybridization
 Linkage analysis
 EST
 Positional cloning
 Molecular Genetics
techniques
 MENDELIAN INHERITANCE
Characteristic Dominant allele
axial or terminal flowers axial flowers

round or wrinkled seeds round seeds

yellow or green seed interiors yellow interiors

violet or white petals violet petals

tall or dwarf plants tall plants

fat or shrunken ripe seed pods fat pods

green or yellow unripe pods green pods

 Mendel’s law of
segregation of
genes

 This law states that

allele pairs separate or
segregate during gamete
formation, and randomly
unite at fertilization
THE LAW OF INDEPENDENT
ASSORTMENT
 This law states that allele pairs
separate independently during the
formation of gametes. Therefore,
traits are transmitted to offspring
independently of one another.
PEDIGREE
A pedigree is a diagram of
family relationships over
several generations

It uses symbols to represent

people and lines to represent
genetic relationships.
These diagrams make it easier to
visualize relationships within
families, particularly large extended
families.

Pedigrees are often used to determine

the mode of inheritance.
Autosomal or x-linked
dominant, or recessive
                                                   

             
DETERMINE IF THE PEDIGREE CHART
SHOWS AN AUTOSOMAL OR X-LINKED
DISEASE.

 If most of the males in the pedigree

are affected the disorder is X-linked

 If it is a 50/50 ratio between men and

women the disorder is autosomal.
IS IT AUTOSOMAL OR X-LINKED?
DETERMINE WHETHER THE
DISORDER IS DOMINANT OR
RECESSIVE
Ifthe disorder is dominant, one of the
parents must have the disorder.

If the disorder is recessive, neither

parent has to have the disorder because
they can be heterozygous.
INTERPRETING PEDIGREE
 Dominant or Recessive?
 SUMMERY PEDIGREES
 Pedigrees are family trees that
explain your genetic history.
 Pedigrees are used to find out
the probability of a child having
a disorder in a particular family.
 To begin to interpret a pedigree,
determine if the disease or
condition is autosomal or X-
linked and dominant or
recessive.
FACTORS AFFECTING
PEDIGREE PATTERNS
 Age of onset
Genetics and Congenital

 Accuracy of information
 Family size

 New mutation

 Variable expression of the gene

 Linkage
PLEIOTROPY

Mutations in one gene may have many possible effects.

Problems in tracing the passage of a mutant allele through
a pedigree can arise when different members of a family
express a different subset of the symptoms. In the case of
Tuberous sclerosis, an autosomal dominant condition
affecting about 1 in 6000 people in the UK, symptoms can
include any subset of:
 small depigmented patches on the skin
 a disfiguring facial rash
 kidney cysts
 heart tumours
 mild to severe mental subnormality
 autism
MITOCHONDRIAL INHERITANCE
 Only maternal transmission
 Very few genetic disorders

 Distinctive pattern
 Uniparental disomy
Rare cases of cystic fibrosis (a common autosomal recessive

disease) have occurred in which one parent was a heterozygous

carrier of the disease but the second parent had two wild type

alleles. The child had received two copies of the mutant

chromosome 7 from the carrier parent and no chromosome 7

from the unaffected parent.

GENERAL CLONING SCHEME
SEQUENCING
HYBRIDIZATION
PCR