From Chimpanzee to Human: Dating Genomic Events in the Human Lineage

1
From Chimpanzee to Human Dating Genomic Events
in the Human Lineage Yuval Itan, CoMPLEX,
UCL Supervisors Mark Thomas, Kevin Bryson,
Charles Lockwood, Ziheng Yang


Introduction In the short evolutionary time since
human and chimpanzee divergence, 5 million years
ago, human acquired traits unique among primates.
These include a tripling of brain size, numerous
cognitive abilities, complex culture, a unique
larynx leading to speech, bipedalism, longlivity,
specific diseases, inferior olfaction.

• Stage II Dating Human Lineage Events
• For inparalogues, will estimate duplication dates
  using chimp orthologue as outgroup. PAML package
  (Yang, 1997) will be used to batch process
  inparalogues and estimate node dates by maximum
  likelihood.
• For pseudogeninization events, will estimate date
  when synonymous / nonsynonymous substitution
  ratio - (dN/dS) became 1, employing different
  programmes from PAML, and will be adapted to
  process batches of candidate pseudogeninization
  events.

• Stage I Finding Human-Specific Events
• Finding human specific duplications
  (inparalogues) using Inparanoid (figure 2)

(b)
(a)
Many of these changes are likely to be caused by
2 specific classes of genomic events in the human
lineage gene duplications, leading to higher
expression levels, and pseudogeneization (usually
caused by frame-shift mutations or premature stop
codons), leading to loss of function. For both of
these classes of change, by using publicly
available human, chimp and macaque genomes, it is
now possible to estimate when the genomic events
took place in the last 5 million years.


Figure 2 Illustration of inparalogues finding
using Inparanoid (OBrien, Remm and Sonnhammer,
2005). Inparalogue is a gene duplication
occurring after a speciation event. A, B and C
represent 3 different species. Genes C2 and C3
are inparalogues, B1 and B2 are outparalogues,
while B1 and C1 are orthologues.

• Stage III Clustering the Times
• After estimating the date for each human specific
  gene, their distribution along the timeline from
  human-chimp divergence until today will be
  checked. A partitional clustering algorithm will
  be applied, and the significance of these
  clusters will be determined. For inparalogues, it
  will be necessary to apply a correction for gene
  conversion.
• Checking distribution of dates along human
  timeline, comparing the results to
  palaeoanthropology research- human fossil record
  dates.

(a)
(b)
Figure 1 The hominid family tree since
human-chimp divergence. From Tattersall and
Schwartz, 2000.
Figure 3 Following Wang, Grus and Zhang, 2006.
(a) The process of filtering human specific
pseudogenes from all human pseudogenes set-
selecting non-processed, truncated, and then
comparing with coding chimp genes. (b) Functional
genes and pseudogenes are represented by open and
closed circles, respectively. Only cases A and B
are considered as human specific pseudogenes.

• Expected Results and Further Work
• Based on the fossil record, expect to find a
  significant clustering of human specific genomic
  changes around times which are key periods in
  human evolution. Previous genetic studies have
  estimated dates of 2.4 mya (correlating to myosin
  heavy chain inactivation in humans, a key factor
  in the evolution of the large human brain) or
  200,000 years ago (FOX2P fixation- language
  development). A schematic example
• Significant clustering in times which do not
  correlate to fossil record will set a truly
  fascinating challenge.
• Further work correlating functionalities of
  genes with dates and fossil record. The set of
  genes unique in human evolution can be used for a
  large array of practical and theoretical studies.

Objective The major hypothesis of this research
is that these human genomic changes are not
distributed randomly on the timeline leading from
human-chimp divergence to the present, but rather
they are clustered. Should this hypothesis be
supported, the second phase of this project will
be to look for correlations between the timing of
these mutation event clusters and key periods in
the evolution of modern humans, as evidenced from
the fossil record. This will relate fossil record
(anthropology) to genomics for the first time on
such a scale. Furthermore, knowledge of the
functions of genes undergoing these mutation
events at key periods in human evolution should
greatly enhance our understanding of the
evolution of human specific phenotypes.

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