Mitochondrial genome. Mitochondria Human mitochondrial DNA Multicopy (466-806 nucleoids /cell) 16,569 bp length and 0.68 M diameter Genes lack introns.

Mitochondrial genome

Mitochondria

Human mitochondrial DNA

• Multicopy (466-806 nucleoids /cell)• 16,569 bp length and 0.68M diameter• Genes lack introns• Maternally inherited• Sequenced in 1981 (Nature,1981, 290:457-65)• Mutation rate ~1/33 generations• Heteroplasmy (original and mutated

forms co-exist)• More stable for forensic analysis

Organization of human mitochondrial DNA.

44% GC heavy (H) – G-rich and light (L) strand – C rich

37 genes distributed, of which 28 genes have H as sense strand 9 genes have L as sense strand

24 genes encode mature RNA 13 encode enzymes involved in oxidative phosphorylation

Mitochondrial genetic code

vertebratesCodon Mitochondrial Universal UGA Tryptophan Stop

AUA Methionine Isoleucine

AGA Stop Arginine

AGG Stop Arginine

D - loopHighest variation in D-loop control regionorigin of replication of the H strand (OH)

two promoters, the heavy-strand (HSP) and the light-strand (LSP) promoter

divided into three domains: the central domain (conserved in evolution but function unknown) two peripheral domains (variable, conserved sequence box (CSB)) extended termination-associated sequences (ETAS) domains

sequential development of ageing mechanisms

Mt encephalomyopathies

• Mutations in every 20-50,000 individuals

• Clinical heterogeneity due to heteroplasmy

• Mostly affects post-mitotic tissues with high oxidative demands like muscle and neurons

Apoptosis

Free radicalsAging

Cancer

NeurodegenerationDiabetes

Mitochondrial disordersPoint mutations-MELAS (Mitochondrial

encephalomyopathy with lactic acidosis & stroke)general short stature, deafness and epilepsyDiabetes mellitus, pigmentary retinopathy and recurrent strokes.A-G transition at nt3243 in mt-tRNALeu(UUR) gene

Diabetes and deafness: 1.5% of all NIDDM unusual mutation in 12S rRNA gene at nucleotide position 1555hearing loss induced after contact with aminoglycosides

Mitochondrial disordersLeber hereditary optic neuropathy (LHON) ophthalmological disorder, presenting mainly

in young adult males characterized by acute or subacute bilateral

optic atrophy resulting in loss of central vision. >90% of affected families have mutations at

nucleotides 11778, 3460 or 14484, that encode components of complex I of the respiratory chain.

Highly unusual in that majority of mutations are present in the homoplasmic state

Also unusual is that incomplete penetrance is seen

Mitochondrial ‘Eve’Mitochondrial ‘Eve’• Recent African Origin Model suggests that our Recent African Origin Model suggests that our

species evolved from a small African population species evolved from a small African population that subsequently colonised the whole worldthat subsequently colonised the whole world

• Coalescence analysis indicates that all mtDNA in Coalescence analysis indicates that all mtDNA in modern humans can be traced back to a single modern humans can be traced back to a single female (~100-150,000 years ago)female (~100-150,000 years ago)

The sex chromosomes

“the most compelling little scrap of stuff in existence.”

The sex chromosomes

There is no universal system of sex determination; can be either genetic or environmental

Humans and fruit flies have the XY genetic system

Y chromosome “single-issue” chromosome designed to determine sex

X chromosome – ‘controlling’

For males, it’s the curse of the ‘lone X’

Females also prone to certain conditions

Sex chromosomes

XX:XY (males heterogametic)ZZ:ZW (females heterogametic)

Variations include X1X2Y or XY1Y2

sex-specific chromosomes tend to be small and gene-poor overall, but might be relatively enriched for genes specifically benefiting the sex that harbours them.

The sex chromosomes In any given species, cytogenetic pattern between homologous chromosomes is similarIn most species however, sex chromosomes tend to be heteromorphic (variations in shape, size and gene content)Gene clustering patterns are also different

Y chromosome

‘hall of mirrors’ – full of palindromes

50Mb size - ~50 genes2 domainsPseudoautosomal region (PAR) – 5%Non-recombining regions (NRY) – 95%

HMG3 pages 367-372

Genetic system

Active genes on the human Y chromosome

Yellow bar, euchromatic NRY (non-recombining region); black bar, heterochromatic portion of NRY; red bars, pseudoautosomal regionsGenes to right: active X-chromosome homologues.Genes to left: lack known X homologues. Genes in red: widely expressed housekeeping genes; genes in black: expressed only in testis genes in green are expressed neither widely, nor testis specifically AMELY (amelogenin Y) is expressed in developing tooth buds, PCDHY (protocadherin Y) is expressed in the brain)

Y chromosome shows the accumulation of spermatogenesis genes and an overall functional decay typical of male-specific chromosomes. active genes on NRY region classed into 3 types on the basis of tissue expression and homology to the X Class 1: housekeeping genes with ancient homology to X Class 2: testis-specific genes. Class 3: genes variously similar to both classes 1 and 2, as well as other genes that might be decaying towards pseudogene status, or the persistence of which might reflect additional evolutionary factors at work on the Y chromosome. Genes that belong to classes 1 and 2 seem to underlie the medical disorders Turner syndrome and male infertility, respectively.

Sex chromosomes of diverse life forms are strikingly alike

Ever-hemizygous chromosomes (Y/W) tend to be small, gene-poor and rich in repetitive sequence.

Their non-sex-specific partners (X/Z) tend to be more autosome-like in form and content, and in many cases undergo dosage compensation to equalize gene activity between the sexes

This gross convergence of sex chromosomes

among disparate lineages hints that common factors drive their evolution.

Human sex-chromosome evolution

• Shrinkage of the Y chromosome• Blockwise expansion of NRY (red regions)• PCDX/Y translocated from X to the NRY (green regions)