Topics covered



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Topics covered

  • Overview of similarities between the genetic makeup of humans and chimpanzees.

  • Comparison of brain and speech genes between humans and chimpanzees

  • Brief overview on the evaluation of the genes.



Why do we need to compare the genomes?

  • Clues to diseases: It demonstrate that the human and chimpanzee species have tolerated more deleterious mutations than other mammals. This confirms an important evolutionary prediction, and may account for greater innovation in primates than rodents, as well as a high incidence of genetic diseases. The genomes contained hints that the chimpanzee genetic code has been attacked more frequently than humans by retroviral elements — such as those present in the HIV virus.



Similarities

  • The chimpanzee( Pan troglodytes) and human genomes are strikingly similar and encode very similar proteins. The DNA sequence that can be directly compared between the two genomes is almost 99 percent identical. When DNA insertions and deletions are taken into account, humans and chimpanzees still share 96 percent sequence identity.

  • At the protein level, 29 percent of genes code for the same amino sequences in chimpanzees and humans. Image obtained from http://usinfo.state.gov/gi/Archive/2005/Sep/01-272693.html



Differences-Brain

  • Brain genes key: A comparison of gene expression in various tissues indicated that most of the genetic changes occurring during the evolution of chimps and humans had neither a positive nor a negative effect. However, the testes in the males of both species showed strong evidence of a positive effect. Also, genes active in the brain showed much more accumulated change in humans than in chimps — suggesting that those genes played a special role in human evolution.



  • Genes related to brain growth

  • Microcephalin and ASPM genes are related to growth of the brain. Microcephalin is a gene determining human brain size in molecular evolution. Microcephalin 1 (or MCPH1) is expressed in the fetal brain, in the developing forebrain, and on the walls of the lateral ventricles. Cells of this area divide, producing neurons that migrate to eventually form the cerebral cortex.



ASPM gene

  • In a study, the researchers focused on a gene called the Abnormal Spindle-Like Microcephaly Associated (ASPM) gene. Loss of function of the ASPM gene is linked – to severe reduction in the size of the cerebral cortex, the part of the brain responsible for planning, abstract reasoning and other higher brain function. Researchers compared the sequence of the human ASPM gene to that from six other primate species shown genetically to represent key positions in the evolutionary hierarchy leading to Homo sapiens. Those species were chimpanzee, gorilla, orangutan, gibbon, macaque and owl monkey.



hhttp://www.plantbio.uga.edu/courses/pbio1210/evolutionetc.html

  • Scientists focused on detecting sequence changes in two genes - Microcephalin and “abnormal spindle-like microcephaly associated” (ASPM) - across different human populations. In humans, mutations in either of these genes can render the gene nonfunctional and cause microcephaly - a clinical syndrome in which the brain develops to a much smaller size than normal.



Lahn and his findings

  • In order to identify sequence changes that occurred in Microcephalin and ASPM in the evolutionary lineage leading to humans, Lahn and his colleagues took the following approach: They determined the DNA sequences of the two genes among a large number of primate species and searched for sequence differences between humans and nonhuman primates. By doing statistical analysis on these sequence differences, they could demonstrate that the differences were due to natural selection that drove significant sequence changes in the lineage leading to humans. These changes accumulated presumably because they conferred some competitive advantage.



Speech

  • The association between Foxp2 and language was first identified in a family in which half the members had severe speech and grammar impairments. Studies showed that all the affected family members had a mutation in the Foxp2 gene.

  • The gene is found on a region of chromosome 7 that is linked to other disorders that affect speech, including autism and specific language impairment (a broad diagnosis used to describe communication difficulties in the absence of mental retardation, hearing loss, or emotional disorders).

  • http://www.eurekalert.org/pub_releases/2005-06/tmsh-ssl062105.php



Analysis of the speech gene

  • Silent and replacement nucleotide substitutions mapped on a phylogeny of primates. Bars represent nucleotide changes. Grey bars indicate amino-acid changes - after reference. The mouse FOXP2 differs in just one amino acid from these three species. Human FOXP2 differs from gorilla & chimp in two further amino acids (and thus differs from mouse in three amino acids).



Gene evolution

  • We began by identifying a set of 13,454 pairs of human and chimpanzee genes with unambiguous 1:1 orthology for which it was possible to generate high-quality sequence alignments covering virtually the entire coding region. The list contains a large fraction of the entire complement of human genes, although it under-represents gene families that have undergone recent local expansion(such as olfactory receptors and immunoglobulins). To facilitate comparison with the lineage, a set of 7,043 human, chimpanzee, mouse and rat genes with unambiguous 1:1:1:1orthology and high-quality sequence alignments was compiled.



Rate of Evolution

  • Rate of Evolution

  • To assess the rate of evolution for each gene, estimated KA, is the number of coding base substitutions that result in amino acid change as a fraction of all such possible sites. Because the background mutation rate varies across the genome, it is crucial to normalize KA for comparisons between genes. A striking illustration of this variation is the fact that the mean KA is 37% higher in the rapidly diverging distal 10Mb of chromosomes than in the more proximal regions. Classically, the background rate is estimated by KS, the synonymous substitution rate (coding base substitutions that, because of codon redundancy, do not result in amino acid change).



  • KA/KS

  • Because a typical gene has only a few synonymous changes between humans and chimpanzees, and not infrequently is zero, we exploited the genome sequence to estimate the local intergenic substitution rate, KI, where appropriate. KA and KS were also estimated for each lineage separately using mouse and rat . The KA/KS ratio is a classical measure of the overall evolutionary constraint on a gene, where KA/KS << 1 indicates that a substantial proportion of amino acid changes must have been eliminated by purifying selection. Under the assumption that synonymous substitutions are neutral, KA/KS > 1 implies, but is not a necessary condition for, adaptive or positive selection.



  • The KA/KS ratio for the human–chimpanzee lineage (hominid) is 0.23. Similarly, KA/KI was also estimated as 0.23. Under the assumption that synonymous mutations are selectively neutral, the results imply that 77% of amino acid alterations in hominid genes are sufficiently deleterious as to be eliminated by natural selection. Because synonymous mutations are not entirely neutral, the actual proportion of amino acid alterations with deleterious consequences may be higher.





Human–chimpanzee–mouse–rat tree with branch-specific KA/KS (q) values. a.Evolutionary tree. The branch lengths are proportional to the absolute rates of amino acid divergence.

  • Human–chimpanzee–mouse–rat tree with branch-specific KA/KS (q) values. a.Evolutionary tree. The branch lengths are proportional to the absolute rates of amino acid divergence.

  • b. Maximum-likelihood estimates of the rates of evolution in protein-coding genes for humans, chimpanzees, mice and rats. Hominid is the KA/KS of the combined human and chimpanzee branches and murid of the combined mouse and rat branches. The slight difference between human and chimpanzee is not statistically significant; masking of some heterozygous bases in the chimpanzee sequence may contribute to the observed difference





  • Thank You




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