Mitochondrial genome

1. Mitochondrial genome

2. Mitochondria

3. Human mitochondrial DNA • Multicopy (466-806 nucleoids /cell) • 16,569 bp length and 0.68mM 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

4. 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

5. Mitochondrial genetic code vertebratesCodon Mitochondrial Universal UGA Tryptophan Stop AUA Methionine Isoleucine AGA Stop Arginine AGG Stop Arginine

6. D - loop Highest variation in D-loop control region origin 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

7. sequential development of ageing mechanisms

8. 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 Aging Free radicals Cancer Diabetes Neurodegeneration

9. Mitochondrial disorders Point mutations-MELAS (Mitochondrial encephalomyopathy with lactic acidosis & stroke) general short stature, deafness and epilepsy Diabetes 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 1555 hearing loss induced after contact with aminoglycosides

10. Mitochondrial disorders Leber 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

11. Mitochondrial ‘Eve’ • Recent African Origin Model suggests that our species evolved from a small African population that subsequently colonised the whole world • Coalescence analysis indicates that all mtDNA in modern humans can be traced back to a single female (~100-150,000 years ago)

12. The sex chromosomes “the most compelling little scrap of stuff in existence.”

13. 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

14. 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.

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

16. Y chromosome ‘hall of mirrors’ – full of palindromes 50Mb size - ~50 genes 2 domains Pseudoautosomal region (PAR) – 5% Non-recombining regions (NRY) – 95% HMG3 pages 367-372

17. Genetic system

18. Active genes on the human Y chromosome Yellow bar, euchromatic NRY (non-recombining region); black bar, heterochromatic portion of NRY; red bars, pseudoautosomal regions Genes 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)

19. 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.

20. 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.

21. 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)