Transcript Document

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/tmshssl062105.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
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.
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