Establishing the Evolutionary Framework for Human Gene Evaluation The first goal is to construct the most accurate molecular phylogeny of as many primate species as possible. Until now, the phylogenetic hierarchy of primate species has only modest local (family and genus level) molecular resolution with little consensus on overall primate radiations. The exact number of primate genera is controversial and species counts range from 261-377. Although whole genome sequencing of 12 primate species are now completed, or nearly so, broader genome representation of mans closest relatives is necessary to interpret human evolution, adaptation and genome structure to assist in biomedical advances. We have accomplished this objective in 2011 and published the first comprehensive and definitive primate phylogeny (Perelman et al 2011). We employed large-scale sequencing and extensive taxon sampling. Approximately half of the 261-377 species and 90% of the genera are included facilitating resolution of long-standing phylogenetic ambiguities. We used high-throughput Sanger sequencing of 54 gene regions from autosome and the X and Y sex chromosomes generating over 8.35 Mb of new data. We provide a highly resolved phylogeny that affirms, reforms and extends previous depictions of primate speciation. In turn, the clarity of the primate phylogeny forms a solid framework for a novel depiction of diverse patterns of genome evolution among primate lineages. Application of Evolutionary Genomics to Human Disease-Associated Genes The second phase is to apply this primate specimen collection and the derivative molecular phylogeny to directly target mutations within human breast cancer genes, as well as AIDS-associated genes. The focus on breast cancer stems from LGD initial sequence investigation of BRCA2 in non-human primates included as part of the data published in Perelman et al. This study will be expanded to address known mutations in BRCA1&2 characterized in human breast cancer tumors. The second area of research will be HIV infection inspired by the foundation established by LGD researchers in characterization of AIDS Restriction Genes, GWAS studies, and newly defined genes in HIV-dependency factors (HDF) including Nuclear Encoded Mitochondrial Proteins (NEMP). The biological import of the genes are not well-known, nor are they members of intensively studied gene complexes such as KIR or HLA which would hinder amplification of the proper ortholog in non-human primates. Further, LGD has a long association with established HIV clinical cohorts, and these are available for follow-up to investigate the functional implications of the initial evolutionary genomic assessment. LGD will use genomic methods with these candidate genes to capture the evolutionary patterns of genetic diversity maintained normal function as compared with mutations linked with disease. In biomedical research, translation to drug development and therapeutics is the desired outcome of genomic analyses. A fine-scale analysis of each candidate gene function will assess the impact of mutations linked with disease.
|Perelman, Polina; Johnson, Warren E; Roos, Christian et al. (2011) A molecular phylogeny of living primates. PLoS Genet 7:e1001342|
|Eizirik, Eduardo; Murphy, William J; Koepfli, Klaus-Peter et al. (2010) Pattern and timing of diversification of the mammalian order Carnivora inferred from multiple nuclear gene sequences. Mol Phylogenet Evol 56:49-63|
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