mitochondrial genome
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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)
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