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Colon cancer associated genes exhibit signatures of positive selection at functionally significant positions.

ABSTRACT: BACKGROUND: Cancer, much like most human disease, is routinely studied by utilizing model organisms. Of these model organisms, mice are often dominant. However, our assumptions of functional equivalence fail to consider the opportunity for divergence conferred by ~180 Million Years (MY) of independent evolution between these species. For a given set of human disease related genes, it is therefore important to determine if functional equivalency has been retained between species. In this study we test the hypothesis that cancer associated genes have different patterns of substitution akin to adaptive evolution in different mammal lineages. RESULTS: Our analysis of the current literature and colon cancer databases identified 22 genes exhibiting colon cancer associated germline mutations. We identified orthologs for these 22 genes across a set of high coverage (>6X) vertebrate genomes. Analysis of these orthologous datasets revealed significant levels of positive selection. Evidence of lineage-specific positive selection was identified in 14 genes in both ancestral and extant lineages. Lineage-specific positive selection was detected in the ancestral Euarchontoglires and Hominidae lineages for STK11, in the ancestral primate lineage for CDH1, in the ancestral Murinae lineage for both SDHC and MSH6 genes and the ancestral Muridae lineage for TSC1. CONCLUSION: Identifying positive selection in the Primate, Hominidae, Muridae and Murinae lineages suggests an ancestral functional shift in these genes between the rodent and primate lineages. Analyses such as this, combining evolutionary theory and predictions - along with medically relevant data, can thus provide us with important clues for modeling human diseases.

SUBMITTER: Morgan CC

PROVIDER: S-EPMC3563467 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Colon cancer associated genes exhibit signatures of positive selection at functionally significant positions.

Morgan Claire C CC Shakya Kabita K Webb Andrew A Walsh Thomas A TA Lynch Mark M Loscher Christine E CE Ruskin Heather J HJ O'Connell Mary J MJ

BMC evolutionary biology 20120712

<h4>Background</h4>Cancer, much like most human disease, is routinely studied by utilizing model organisms. Of these model organisms, mice are often dominant. However, our assumptions of functional equivalence fail to consider the opportunity for divergence conferred by ~180 Million Years (MY) of independent evolution between these species. For a given set of human disease related genes, it is therefore important to determine if functional equivalency has been retained between species. In this s ...[more]

PMID: 22788692

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Project description:BACKGROUND: Toll-like receptors (TLRs) are a major class of pattern recognition receptors (PRRs) expressed in the cell surface or membrane compartments of immune and non-immune cells. TLRs are encoded by a multigene family and represent the first line of defense against pathogens by detecting foreigner microbial molecular motifs, the pathogen-associated molecular patterns (PAMPs). TLRs are also important by triggering the adaptive immunity in vertebrates. They are characterized by the presence of leucine-rich repeats (LRRs) in the ectodomain, which are associated with the PAMPs recognition. The direct recognition of different pathogens by TLRs might result in different evolutionary adaptations important to understand the dynamics of the host-pathogen interplay. Ten mammal TLR genes, viral (TLR3, 7, 8, 9) and non-viral (TLR1-6, 10), were selected to identify signatures of positive selection that might have been imposed by interacting pathogens and to clarify if viral and non-viral TLRs might display different patterns of molecular evolution. RESULTS: By using Maximum Likelihood approaches, evidence of positive selection was found in all the TLRs studied. The number of positively selected codons (PSC) ranged between 2-26 codons (0.25%-2.65%) with the non-viral TLR4 as the receptor with higher percentage of positively selected codons (2.65%), followed by the viral TLR8 (2.50%). The results indicated that viral and non-viral TLRs are similarly under positive selection. Almost all TLRs have at least one PSC located in the LRR ectodomain which underlies the importance of the pathogen recognition by this region. CONCLUSIONS: Our results are not in line with previous studies on primates and birds that identified more codons under positive selection in non-viral TLRs. This might be explained by the fact that both primates and birds are homogeneous groups probably being affected by only a restricted number of related viruses with equivalent motifs to be recognized. The analyses performed in this work encompassed a large number of species covering some of the most representative mammalian groups - Artiodactyla, Rodents, Carnivores, Lagomorphs and Primates - that are affected by different families of viruses. This might explain the role of adaptive evolution in shaping viral TLR genes.

Project description:Sialic acids are nine carbon sugars ubiquitously found on the surfaces of vertebrate cells and are involved in various immune response-related processes. In humans, at least 58 genes spanning diverse functions, from biosynthesis and activation to recycling and degradation, are involved in sialic acid biology. Because of their role in immunity, sialic acid biology genes have been hypothesized to exhibit elevated rates of evolutionary change. Consistent with this hypothesis, several genes involved in sialic acid biology have experienced higher rates of non-synonymous substitutions in the human lineage than their counterparts in other great apes, perhaps in response to ancient pathogens that infected hominins millions of years ago (paleopathogens). To test whether sialic acid biology genes have also experienced more recent positive selection during the evolution of the modern human lineage, reflecting adaptation to contemporary cosmopolitan or geographically-restricted pathogens, we examined whether their protein-coding regions showed evidence of recent hard and soft selective sweeps. This examination involved the calculation of four measures that quantify changes in allele frequency spectra, extent of population differentiation, and haplotype homozygosity caused by recent hard and soft selective sweeps for 55 sialic acid biology genes using publicly available whole genome sequencing data from 1,668 humans from three ethnic groups. To disentangle evidence for selection from confounding demographic effects, we compared the observed patterns in sialic acid biology genes to simulated sequences of the same length under a model of neutral evolution that takes into account human demographic history. We found that the patterns of genetic variation of most sialic acid biology genes did not significantly deviate from neutral expectations and were not significantly different among genes belonging to different functional categories. Those few sialic acid biology genes that significantly deviated from neutrality either experienced soft sweeps or population-specific hard sweeps. Interestingly, while most hard sweeps occurred on genes involved in sialic acid recognition, most soft sweeps involved genes associated with recycling, degradation and activation, transport, and transfer functions. We propose that the lack of signatures of recent positive selection for the majority of the sialic acid biology genes is consistent with the view that these genes regulate immune responses against ancient rather than contemporary cosmopolitan or geographically restricted pathogens.

Project description:BackgroundCurrently, there is very limited knowledge about the genes involved in normal pigmentation variation in East Asian populations. We carried out a genome-wide scan of signatures of positive selection using the 1000 Genomes Phase I dataset, in order to identify pigmentation genes showing putative signatures of selective sweeps in East Asia. We applied a broad range of methods to detect signatures of selection including: 1) Tests designed to identify deviations of the Site Frequency Spectrum (SFS) from neutral expectations (Tajima's D, Fay and Wu's H and Fu and Li's D* and F*), 2) Tests focused on the identification of high-frequency haplotypes with extended linkage disequilibrium (iHS and Rsb) and 3) Tests based on genetic differentiation between populations (LSBL). Based on the results obtained from a genome wide analysis of 25 kb windows, we constructed an empirical distribution for each statistic across all windows, and identified pigmentation genes that are outliers in the distribution.ResultsOur tests identified twenty genes that are relevant for pigmentation biology. Of these, eight genes (ATRN, EDAR, KLHL7, MITF, OCA2, TH, TMEM33 and TRPM1,) were extreme outliers (top 0.1% of the empirical distribution) for at least one statistic, and twelve genes (ADAM17, BNC2, CTSD, DCT, EGFR, LYST, MC1R, MLPH, OPRM1, PDIA6, PMEL (SILV) and TYRP1) were in the top 1% of the empirical distribution for at least one statistic. Additionally, eight of these genes (BNC2, EGFR, LYST, MC1R, OCA2, OPRM1, PMEL (SILV) and TYRP1) have been associated with pigmentary traits in association studies.ConclusionsWe identified a number of putative pigmentation genes showing extremely unusual patterns of genetic variation in East Asia. Most of these genes are outliers for different tests and/or different populations, and have already been described in previous scans for positive selection, providing strong support to the hypothesis that recent selective sweeps left a signature in these regions. However, it will be necessary to carry out association and functional studies to demonstrate the implication of these genes in normal pigmentation variation.

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Colon cancer associated genes exhibit signatures of positive selection at functionally significant positions.

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Colon cancer associated genes exhibit signatures of positive selection at functionally significant positions.

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