1. Mitochondrial genome

2. Mitochondria
Schematic representation of the mitochondrion with details of the inner membrane and its respiratory complexes (I–IV). Mitochondria are formed by two membranes, an outer membrane having mainly permeability properties and an inner membrane where electron transport and oxidative phosphorylation occur. The inner space, called matrix, contains metabolic enzymes, the mitochondrial deoxyribonucleic aci ...

3. Human mitochondrial DNA
Multicopy ( 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
~2-10 genomes / nucleoid)

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
Figure 2  Organization of human mitochondrial DNA. The two strands are called heavy (H) and light (L) according to their isopycnic sedimentation in a cesium chloride gradient. Gene distribution between the two strands and the main regulatory regions is indicated. The protein-coding genes are: ATP6, ATP8: ATPase subunits; CO I, II, III: cytochrome c oxidase subunits; Cytb: cytochrome b; 1, 2, 3, 4, 4L, 5, 6: NADH dehydrogenase subunits; 12S, 16S rRNAs: small and large ribosomal subunits RNA; A: alanine; C: cysteine; D: aspartic acid; E: glutamic acid; F: phenylalanine; G: glycine; H: histidine; I: isoleucine; K: lysine; L: leucine; M: methionine; N: asparagine; P: proline; Q: glutamine; R: arginine; S: serine; T: threonine; V: valine; W: tryptophan; Y: tyrosine transfer RNA genes; OL: L strand replication origin; OH: H strand replication origin. In the expanded D-loop region – HSP: H strand promoter; LSP: L strand promoter; CSB: conserved sequence box; ETAS: extended termination associated sequences; LR and SR: short and long repeats; the conserved central domain (black bar), the RNA primer (gray) and the RNA/DNA transition are indicated.

5. Mitochondrial genetic code
vertebrates Codon 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
The sequential development of ageing mechanisms.   Modelling can reveal how the mechanisms responsible for cellular ageing can develop sequentially as the process advances6. In simulations, it is found that a long period of gradual accumulation of mitochondrial (mt)DNA mutations results in a progressive increase in intracellular stress and a decline in energy production that eventually precipitates a more pronounced breakdown of cellular homeostasis.

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
Several mutations have been associated uniquely with sensorineural hearing loss, including one unusual mutation
in the 12S rRNA gene at nucleotide position This mutation induces hearing loss when patients harbouring
the substitution come into contact with common aminoglycosides that may have been used to treat bacterial
infection. This novel pathogenic mechanism is believed to be due to an increased affinity for the aminoglycoside,
which binds to the rRNA and interferes with normal mitochondrial protein synthesis.

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
If the point mutation is found in all copies of mtDNA in all cells and tissues, why is the optic nerve the only affected tissue? Retinal ganglion cells and the optic nerve are believed to be exquisitely sensitive to mitochondrial dysfunction Evidence in favour of this hypothesis comesfrom an unusual source. About 40 years ago, a cohort of children suffering from cystic fibrosis was treated with chloramphenicol, an inhibitor of mitochondrial protein synthesis. Numerous children developed ophthalmological problems that were remarkably similar to the symptoms of LHON, and these symptoms were reversed when the treatment was halted. It is striking that the systemic use of a mitochondrial translation inhibitor caused a similar tissue-selective clinical defect to that observed with a homoplasmic mtDNA mutation.

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 (~ ,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.
Owing to reduced recombination, 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. ‘hall of mirrors’ – full of palindromes
Y chromosome
‘hall of mirrors’ – full of palindromes
50Mb size - ~50 genes
2 domains
Pseudoautosomal region (PAR) – 5%
Non-recombining regions (NRY) – 95%
Sex chromosomes have arisen many times in the living world and show striking examples of convergent similarity that reflect shared evolutionary modes in the emergence and maintenance of chromosomal sex determination. Owing to reduced recombination, 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 human X and Y chromosomes are the best-characterized sex-chromosome system. They have progressively diverged from each other, via blockwise recession of their mutually recombining regions towards each telomere, probably mediated by large-scale inversions of intervening sequence on the Y chromosome in particular. Studies of the human Y chromosome highlight the accumulation of spermatogenesis genes and the overall functional decay typical of male-specific chromosomes. The known active genes on the non-recombining portion of the human Y chromosome sort neatly, on the basis of tissue expression and homology to the X chromosome, into three basic classes. Class 1: housekeeping genes that have withstood the overall decay of the Y chromosome, attesting to its ancient homology with the X chromosome, on which highly similar copies of these genes elude inactivation. Class 2: testis-specific genes — generally recruited to the Y chromosome by translocation or retroposition — that specifically benefit male fitness. 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.
HMG3 pages

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)
Genes named to the right of the chromosome have active X-chromosome homologues. Genes named to the left of the chromosome lack known X homologues. Genes in red are widely expressed housekeeping genes; genes in black are expressed in the testis only; and genes in green are expressed neither widely, nor testis specifically (AMELY (amelogenin Y) is expressed in developing tooth buds, whereas PCDHY (protocadherin Y) is expressed in the brain). With the exception of the SRY (sex-determining region Y) gene, all the testis-specific Y genes are multicopy. Some multicopy gene families form dense clusters, the constituent loci of which are indistinguishable at the resolution of this map. Three regions often found deleted in infertile men, AZFa, b, c (azoospermia factor region a, b, c), are indicated.

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.
Sex chromosomes have arisen many times in the living world and show striking examples of convergent similarity that reflect shared evolutionary modes in the emergence and maintenance of chromosomal sex determination. Owing to reduced recombination, 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 human X and Y chromosomes are the best-characterized sex-chromosome system. They have progressively diverged from each other, via blockwise recession of their mutually recombining regions towards each telomere, probably mediated by large-scale inversions of intervening sequence on the Y chromosome in particular. Studies of the human Y chromosome highlight the accumulation of spermatogenesis genes and the overall functional decay typical of male-specific chromosomes. The known active genes on the non-recombining portion of the human Y chromosome sort neatly, on the basis of tissue expression and homology to the X chromosome, into three basic classes. Class 1: housekeeping genes that have withstood the overall decay of the Y chromosome, attesting to its ancient homology with the X chromosome, on which highly similar copies of these genes elude inactivation. Class 2: testis-specific genes — generally recruited to the Y chromosome by translocation or retroposition — that specifically benefit male fitness. 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
Figure 3 | Human sex-chromosome evolution. The figure shows the overall shrinkage of the Y chromosome and the blockwise expansion of its nonrecombining region (NRY), probably mediated by serial large-scale inversion as posited by Lahn and Page14. Main events are noted and roughly dated (Myr ago,millions of years ago), with new NRY genes placed in parentheses, and phylogenetic branches indicated by arrows. Blue regions are freely recombining. Yellow regions are X-chromosome specific. Red regions are Y-specific (NRY). The green region represents PCDHX/Y (protocadherin X/Y)-containing sequence that has translocated from the X to the NRY (some other likely translocations are omitted for simplicity). The diagram is not drawn to scale and centromeres are omitted, astheir locations are uncertain for many evolutionary stages. (PARp, short arm pseudoautosomal region.)
Shrinkage of the Y chromosome
Blockwise expansion of NRY (red regions)
PCDX/Y translocated from X to the NRY (green regions)