Download Mitochondrial genome

Mitochondrial genome
Mitochondria
Human mitochondrial DNA
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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
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
Codon
UGA
AUA
AGA
AGG
vertebrates
Mitochondrial
Tryptophan
Methionine
Stop
Stop
Universal
Stop
Isoleucine
Arginine
Arginine
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
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
Aging
Free radicals
Diabetes
Neurodegeneration
Cancer
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
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
present in the homoplasmic state
 Also unusual is that incomplete penetrance is
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)
The sex chromosomes
“the most compelling little scrap of stuff in existence.”
The sex chromosomes
There is no universal system; 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 similar
In 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 genes
2 domains
Pseudoautosomal 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 (nonrecombining 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)
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)