Comparison of the Human and Chimpanzee Genomes

Tyler IzattCBS 520

Outline

• Motivation• Whole Genome Comparison• Disease Associated Genes• CNV study

Motivation

• Why study the chimpanzee genome?

– P. Troglodytes is our closest ancestor besides the bonobo

– Aid our understanding of human “uniqueness”

– Disease Research

– Evolution

• Advantages to the chimpanzee genome vs. other genomes

– Less sequence alignment, more comparison of differences.

– Single events vs. Multiple events

– Most differences = random genetic drift

Motivation

• Advantages to the chimpanzee genome vs. other genomes

– Less sequence alignment, more comparison of differences.

– Single events vs. Multiple events

– Most differences = random genetic drift

Timeline

2002 - Draft of the Human Genome Completed2002 - Draft of the Human Genome Completed

2005 – Draft of the Chimpanzee Genome Completed2005 – Draft of the Chimpanzee Genome Completed

Chromosomal Differences

• Several chromosomal differences have been noted from studies dating to the 1980’s

• These include:– Chromosome 2 fusion– Multiple Pericentric inversions

Chromosome 2 Fusion• Chimpanzees have 24 chromosomes.

• A fusion event involving the 2p and 2q chromosomes created Chromosome 2 in humans.

• There are vestigial telomeric regions in the human chromosome supporting this hypothesis.

• DNA evidence also confirms shared homology between the human chromosome 2 and chimp chromosomes (2p, 2q)

Gene Content and Function of the Ancestral Chromosome Fusion Site in Human Chromosome 2q13–2q14.1 and Paralogous RegionsYuxin Fan, , Tera Newman, ,Elena Linardopoulou, and Barbara J. Trask1 -

Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA

Chromosome 2 Fusion

• 150 kb of DNA have also been inserted at this region in humans that are not found in the chimpanzee

The insert includes several potential genes:

– PGML – incomplete Phosphoglutamate gene. – FOXD – transcription factor– CBWD - Cobalamin synthetase is a bacterial

enzyme that makes vitamin B12. This is the first known eukaryotic homolog to the Cobalamin synthetase.

Chimpanzee Genome Draft

• In 2005, the same researchers who released the chimpanzee genome performed a large scale comparison of the human genome vs. the chimpanzee genome.

• Key Findings:– Transposable Elements

• SINES are 3 times more common in humans vs. chimps• Several retroviral families have appeared in chimpanzees

– Genome divergence• Genome divergence was calculated at 1.23% between human

and chimp genomes.

Chimpanzee Genome Draft

• Proteins– 29% of orthologous proteins are identical. Most

orthologous proteins differ only by one or two amino acids.

• This data surprised many people. Most thought that the human and chimp genomes would not be so similar.

http://www.nature.com/nature/journal/v437/n7055/full/nature04072.htmlhttp://www.nature.com/nature/journal/v437/n7055/full/nature04072.html

Disease associated Genes(from 2005 study)

• Caspase-12– This protein triggers apoptosis in response to perturbed calcium

homeostasis in mice. – In chimps caspase-12 is a fully functional gene– However most humans have an inherited allele for a premature

stop codon in the caspase-12 gene.– Studies in mice have shown that caspase-12 could be linked to

Alzheimers disease because it mediates calcuim homeostasis and amyloid beta cytoxicity.

• Reasons for selection for caspase-12– African populations with a functional caspase-12 are more

susceptible to sepsis.

Disease Associated Genes…

• Inflammatory response. Human and chimpanzee show a notable difference with respect to important mediators of immune and inflammatory responses. Three genes ( IL1F7, IL1F8 and ICEBERG) that act in a common pathway involving the caspase-1 gene all appear to be deleted in chimpanzee. ICEBERG is thought to repress caspase-1-mediated generation of pro-inflammatory IL1 cytokines, and its absence in chimpanzee may point to species-specific modulation of the interferon- - and lipopolysaccharide-induced inflammatory response 127.

• Parasite resistance. Similarly, we found that two members of the primate-specific APOL gene cluster (APOL1 and APOL4) have been deleted from the chimpanzee genome. The APOL1 protein is associated with the high-density lipoprotein fraction in serum and has recently been proposed to be the lytic factor responsible for resistance to certain subspecies of Trypanosoma brucei, the parasite that causes human sleeping sickness and the veterinary disease nagana128. The loss of the APOL1 gene in chimpanzees could thus explain the observation that human, gorilla and baboon possess the trypanosome lytic factor, whereas the chimpanzee does not129.

• Sialic acid biology related proteins. Sialic acids are cell-surface sugars that mediate many biological functions130. Of 54 genes involved in sialic acid biology, 47 were suitable for analysis. We confirmed and extended findings on several that have undergone human-specific changes, including disruptions, deletions and domain-specific functional changes113, 131, 132. Human- and chimpanzee-specific changes were also found in otherwise evolutionarily conserved sialyl motifs in four sialyl transferases (ST6GAL1, ST6GALNAC3, ST6GALNAC4 and ST8SIA2), suggesting changes in donor and/or acceptor binding130. Lineage-specific changes were found in a complement factor H (HF1) sialic acid binding domain associated with human disease133. Human SIGLEC11 has undergone gene conversion with a nearby pseudogene, correlating with acquisition of human-specific brain expression and altered binding properties134.

Copy Number Variation

• Most studies have focused on measuring SNP differences or chromosomal differences in genomes.

• The mapping of the Human Genome showed the importance of CNV (Copy Number Variation).

• What is CNV?– The amount of copies of a gene present in the genome. – To be considered a CNV, fragment must be 1 kb or larger (Feuk

et al. 2006)• CNV mutations alter gene dosage as opposed to altering the genetic

code. (example: Down Syndrome)

CNV Study

• A 2008 study analyzed CNVs in the chimp and human genomes• aCGh - Array Comparative Genomic Hybridization

• Researchers used DNA probes from the human genome• DNA from humans and chimps was prepared and labeled

with different fluorescent colors.• Human DNA – a sample of 30 Africans• Chimp DNA – a sample of 30 western chimpanzees

• Euchromatin– 97 % of human euchromatin was covered by the probes.

Whole-genome comparison of human and chimpanzee copy number variation

Perry G. H. et.al. Genome Res. 2008;18:1698-1710

©2008 by Cold Spring Harbor Laboratory Press

CNV Study

– Significant CNV differences – Genes not found in P. Traglodytes:

• Apol1 gene – involved in resistance to protozoan trypanosome parasites that cause sleeping sickness

• CARD8, ILIF7 – These proteins bind to caspase1 and inhibit production of an inflammatory cytokine.

– Oncogenes• TBC1D3

– 8 copies found in H. sapiens– 1 copy found in P. troglodytes

• This study has given us a genome wide CNV map for humans and chimpanzees.

• Limits– DNA probes were used from H. sapiens therefore any

deleted regions in H. Sapiens could not be detected by this method.

Copy number variation and evolution in humans and chimpanzees

George H. Perry, Fengtang Yang, Tomas Marques-Bonet, Carly Murphy, Tomas Fitzgerald3, Arthur S. Lee2, Courtney Hyland2, Anne C. Stone, Matthew E. Hurles, Chris Tyler-Smith, Evan E. Eichler, Nigel P. Carter, Charles Lee, Richard Redon Genome Res. 2008. 18: 1698-1710

Discussion

• Humans and Chimpanzees are more similar than previously thought.

• Understanding phenotypic variation will require using multiple methods.

• Both the Human and Chimpanzee genomes are fully available online. Many researchers are comparing the two genomes because of the relevance to human diseases.

The End