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Genes, Chromosomes and the content of the Human Genome

Scott Lawton Email: Office hours Monday 11 - 12, Friday 9 - 11

LS2100 Concepts in human genetics, School of Life Sciences, Kingston University

Navigating the Human Genome

Learning outcomes
Link DNA with genes and gene structure

Understand the role of chromosomes in packaging genes Appreciate the diversity of chromosomes; their structure and function Familiarise yourself with jargon of the molecular content of the human genome

Overview of lecture
Revision of DNA structure and content Structure and function of genes Packaging of DNA onto chromosomes Structure and function of chromosomes Sex chromosomes

Chromosomes and genetic inheritance

Chromosome theory of inheritance

Mendelian factors - genes are located on chromosomes Not all chromosomes are equal in gene content Autosomes Variable number of genes X chromosomes gene rich Y chromosomes - gene poor

DNA: the building blocks of life?

DNA is self replicating Gives rise to other molecules: Transcription/Translation It can repair itself and form new combinations: Recombination

Composition of DNA
4 base pairs
Purines; Adenine and Guanine Double ring structure Pyrimidines; Cytosine and thymine

Helix supported by the phosphate sugar back bone

Genes: structure
Genes :
A locatable region of genomic sequence, corresponding to a unit of inheritance These are associated with regulatory, transcribed and other functional regions
Exon Intron
Codon Codon Codon Codon
Codon Codon Codon

Exon Intron


Codon Codon Codon Codon


DNA Packaging on the Chromosomes

First level of packaging DNA winds around histones to form the nucleosome Individual nucleosomes are connected by strands of linker DNA and histones knowein as linker histone form chromatin fibres Next level involves the looped domains of DNA - Tens to Hundreds of Kilobase pairs - Average human chromosome = 2000 looped domains - Domans extend at an angle from the main chromosome - Loops anchor on to a filamentous structure of protein nuclear matrix

Euchromatin Makes up the majority of the uncondensed chromosome Transcriptionally active Majority of the active genome Heterochromatin Remain condensed through out cell cycle Replicates later than rest of genome Usually transcriptionally inactive Two types Constitutional Facultative

Chromosome structure

P Arm

Q Arm

Sister chromatids

Chromosome diversity
Metacentric Submetacentric Acrotacentric Telocentric

Human genome: Karyotypes

23 pairs of chromosomes 22 Pairs are homologous 1 pair of sex chromosomes Females XX Males XY

Human genome: Karyotypes

Number Size/ relative size Chromatin content Centromere position

Human genome: Karyotypes

Molecular cytogentics
Fluorescent in situ hybridisation BAC landing Chromosome painting

Chromosomal mutations Deletions Duplications Inversions


Consideration: Human Sex Chromosomes

The sex chromosomes X chromosome is gene rich Reproduction Intelligence
Y chromosome Gene poor Single male determining gene (SRY) Reduced recombination

Highly heterochromatised and degenerate Y chromosomes

Consideration: Human Sex Chromosomes

Evolution of sex chromosomes two homologous chromosomes One chromosome accumulates mutations that are beneficial to a single sex Genes become involved in sex determination Selection reduces recombination Heterochromatisation Inversions Translocations Y chromosome is born and begins to degrade Loses genes Few genes active Becomes transcriptionally in active

Consideration: Human Sex Chromosomes

Genes are packaged on to chromosomes Chromosomes are a heritable unit Karyotype analysis is based on the structure of a the genome Cytogenetics FISH Chromosomal mutation Sex chromosomes unique properties compared to the rest of the genome

Molecular basis of the Human genome

The Human Genome

Most human cells are diploid 2n Somatic cells Gametes cells are haploid n 2n =46 n=23 Somatic cells derived by mitosis Gametes derived by meiosis.

Measuring DNA.
Base pair (bp) Kilobase pairs (kbp or kb) Subdivisions of chromosomes
Bases Sequences Contigs Scaffolds Super Scaffolds


Chromosomes Genomes

Types of DNA Sequences

Human genome: 9 x109 bp /80,000 genes Two main types of DNA in human genome
Nuclear Extranuclear

Distribution varies greatly Few in heterochromatin, majority in sub telomeric euchromatin Made up of single copy genes and multigene families

Unique single copy genes

Majority of human genes Code for polypeptides involved in carrying out a variety of cellular functions
enzymes hormones receptors regulatory proteins structural proteins

Multigene families
Many genes have similar functions: gene duplication with subsequent evolutionary divergence Often found in clusters eg. Globin gene cluster on chromosome 16

Others widely dispersed throught the genome eg. Hox developmental genes.

Gene Superfamilies
Limited sequence homology but share functionality often having similar structural domains. Examples include the immunoglobulin genes which are almost certainly derived from duplication of a precursor gene.

Extragenic DNA
80,000 genes with an average size of 1015kb Account for only 25-35% of the human genome The remaining 70% is made up of repetative DNA sequences which are predominantly transcriptionally inactive.

Tandemly repeated DNA sequences

Blocks of highly repetative non coding DNA which can either be highly dispersed or restricted in their location in the genome. Three sub groups
Satellite DNA Minisatellite DNA Microsatelite DNA

Satelite DNA
10 -15% of human genome Simple short tandemly repeated DNA sequences Transcriptionally inactive Clustered around the centromeres of certain chromosomes Named after the characteristics of this type of DNA in density gradient centrifugation.

Minisatelite DNA
Two families of transcriptionally inactive repeated short DNA sequences Telomeric DNA
The end of telomeres contain 10-15kb of tandem repeats of a 6bp repeat sequence. Chromosomal integrity Telomerase

Minisatellite DNA
Hypervariable minisatelite DNA Highly polymorphic Short tandem repeats of a core sequence Polymorphism in repeat number is the basis for genetic fingerprinting (forensic/paternity) Often located close to telomeres

Microsatelite DNA
Single, di, tri, or tetra nucleotide repeats located througout the genome some trinucleotide repeats are associated with genetic diseases Highly polymorphic and are used to map genes


Highly repeated interspersed repetative DNA sequences.

33% of the human genome Two types
short interspersed nuclear elements.SINEs Long interspersed nuclear elements.LINEs

5% of genomes consists of 750,000 copies of SINEs. Most common is a 300bp repeat which has similarity to a signal recognition particle involved in protein synthesis They are called Alu repeats Retrotransposons are genetic elements that can amplify themselves in a genome and are ubiquitous components of the DNA of many eukaryotic organisms.

5% of genome Most common one is sequence of 6000bp that occur in about 100 000 copies which encodes a reverse transcriptase .

Called LINE-1 or L1 element

Mitochondrial DNA
Every cell has several thousand mitochondria Each mitochondria has its own 16.6kb circular double stranded DNA, mtDNA It has very little repetative DNA and codes for 37 genes Mitochondria are inherited exclusively from the oocyte

A variety of genes with a variety of functions 1 gene = 1 protein Majority of the genome is non coding Vast amounts of the genome is repetitive Mitochondrial DNA organelle, maternally inherited