The Chimpanzee Genome Motivation for sequencing Medical applications Evolutionary studies Informative differences Insertions/Deletions Difference in regulatory regions Different genes SNPs Because the chimpanzee is presumed to be our closest relative, fully sequencing its genome is expected to give us numerous evolutionary and medical insights. The sequencing effort has been greatly facilitated by using the already sequenced human genome to align fragments of the chimpanzee genome. A base-pair by base-pair comparison of chimpanzee and human genomes will uncover the genes, insertions, deletions, differences in regulatory regions, and single nucleotide polymorphisms that make humans unique. Analyzing such differences will reveal a tremendous amount about our evolutionary past and the function of uniquely human genes. From a medical perspective, a number of significant differences between human and chimpanzee biology suggest a variety of medical insights. For example, female chimpanzees never reach menopause in the wild, and chimpanzees in general are much less susceptible to the micro-organism that causes the deadliest form of malaria in humans. Scientists using human-chimpanzee sequence comparisons may thus be able to find genes leading to early infertility, susceptibility to malaria, and other medical problems. At the end of 2003, a draft sequence of the chimpanzee genome was published by a group of sequencing centers in the United States. Benfey Genomics © 2005 Prentice Hall Inc. / A Pearson Education Company / Upper Saddle River, NJ 07458

Progress in sequencing the chimpanzee genome December 2003 First draft completed May 2004 Chimpanzee chromosome 22 sequenced to same accuracy as human genome Chimpanzee chromosome 22 homologous to human chromosome 21 Trisomy 21 in humans results in Down’s syndrome While the draft sequence was in many ways incomplete, in May 2004 a group of Asian and European scientists succeeded in sequencing chimpanzee chromosome 22 to a level of accuracy that matched the fully sequenced human genome. Chimpanzee chromosome 22 is homologous to human chromosome 21. Human chromosome 21 is medically important because trisomy 21 leads to Down’s syndrome, which is among the most common causes of mental retardation. Benfey Genomics © 2005 Prentice Hall Inc. / A Pearson Education Company / Upper Saddle River, NJ 07458

Differences between human and chimpanzee chromosomes Nucleotide substitutions for 1.4% of sequence 68,000 indels Range in size: 30 bp to 54,000 bp Human insertions of ~300 bp due to Alu element 47 protein-encoding genes estimated to have significant structural differences The figure in the slide shows differences between the sequence of chimpanzee chromosome 22 and human chromosome 21. Nucleotide divergence is shown in black and the red line indicates differences in G+C content. The horizontal line at the bottom of the figure indicates the sequence position in the two aligned chromosomes. At the aggregate level, nucleotide substitutions occurred in 1.4% of the sequence and there was evidence of roughly 68,000 insertions/deletions (or “indels”). The size of indels varied from 30 bp to 54,000 bp. Though greater than 99% of the indels were less than 300 bp, longer insertions seemed to be the result of transposable elements, especially Alu elements in the human sequence. 231 putative genes were compared in the chimpanzee and human chromosomes. Of these genes, roughly 10% showed evidence of positive selection when a statistical test that examines base-pair substitutions was applied. The gene determined to have the strongest selection was a protein found in human hair. Amino-acid analysis also suggested significant structural differences in 47 of the 231 genes. Overall, this study has shown that differences between the human and chimpanzee genomes are more complex than previously thought. Figure credit: From Figure 1a in The International Chimpanzee Chromosome 22 Consortium (2004) “DNA sequence and comparative analysis of chimpanzee chromosome 22” Nature 429: 382-388. From Figure 1a in The International Chimpanzee Chromosome 22 Consortium (2004) “DNA sequence and comparative analysis of chimpanzee chromosome 22” Nature 429: 382-388. Benfey Genomics © 2005 Prentice Hall Inc. / A Pearson Education Company / Upper Saddle River, NJ 07458