Browsing by Author "Liao, Ben-Yang"

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Assessing Determinants of Exonic Evolutionary Rates in Mammals
(2012-10-01)
Chen, Feng-Chi
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Liao, Ben-Yang
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Pan, Chia-Lin
;
Lin, Hsuan-Yu
;
Chang, Andrew Ying-Fei
From studies investigating the differences in evolutionary rates between genes, gene compactness and gene expression level have been identified as important determinants of gene-level protein evolutionary rate, as represented by nonsynonymous to synonymous substitution rate (d(N)/d(S)) ratio. However, the causes of exon-level variances in d(N)/d(S) are less understood. Here, we use principal component regression to examine to what extent 13 exon features explain the variance in d(N), d(S), and the d(N)/d(S) ratio of human-rhesus macaque or human-mouse orthologous exons. The exon features were grouped into six functional categories: expression features, mRNA splicing features, structural-functional features, compactness features, exon duplicability, and other features, including G + C content and exon length. Although expression features are important for determining d(N) and d(N)/d(S) between exons of different genes, structural-functional features and splicing features explained more of the variance for exons of the same genes. Furthermore, we show that compactness features can explain only a relatively small percentage of variance in exon-level d(N) or d(N)/d(S) in either between-gene or within-gene comparison. By contrast, d(S) yielded inconsistent results in the human-mouse comparison and the human-rhesus macaque comparison. This inconsistency may suggest rapid evolutionary changes of the mutation landscape in mammals. Our results suggest that between-gene and within-gene variation in d(N)/d(S) (and d(N)) are driven by different evolutionary forces and that the role of mRNA splicing in causing the variation in evolutionary rates of coding sequences may be underappreciated.
Exploring the selective constraint on the sizes of insertions and deletions in 5 ' untranslated regions in mammals
(2011-07-05)
Chen, Chun-Hsi
;
Liao, Ben-Yang
;
Chen, Feng-Chi
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生物科技學系
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Department of Biological Science and Technology
Background: Small insertions and deletions ("indels" with size <= 100 bp) whose lengths are not multiples of three (non-3n) are strongly constrained and depleted in protein-coding sequences. Such a constraint has never been reported in noncoding genomic regions. In 5' untranslated regions (5' UTRs) in mammalian genomes, upstream start codons (uAUGs) and upstream open reading frames (uORFs) can regulate protein translation. The presence of non-3n indels in uORFs can potentially disrupt the functions of these regulatory elements. We thus hypothesize that natural selection disfavors non-3n indels in 5' UTRs when these regulatory elements are present. Results: We design the Indel Selection Index to measure the selective constraint on non-3n indels in 5' UTRs. The index controls for the genomic compositions of the analyzed 5' UTRs and measures the probability of non-3n indel depletion downstream of uAUGs. By comparing the experimentally supported transcripts of human-mouse orthologous genes, we demonstrate that non-3n indels downstream of two types of uAUGs (alternative translation initiation sites and the uAUGs of coding sequence-overlapping uORFs) are underrepresented. The results hold well regardless of differences in alignment tool, gene structures between human and mouse, or the criteria in selecting alternatively spliced isoforms used for the analysis. Conclusions: To our knowledge, this is the first study to demonstrate selective constraints on non-3n indels in 5' UTRs. Such constraints may be associated with the regulatory functions of uAUGs/uORFs in translational regulation or the generation of protein isoforms. Our study thus brings a new perspective to the evolution of 5' UTRs in mammals.
Scanning for the Signatures of Positive Selection for Human-Specific Insertions and Deletions
(2009)
Chen, Chun-Hsi
;
Chuang, Trees-Juen
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Liao, Ben-Yang
;
Chen, Feng-Chi
;
生物科技學系
Human-specific small insertions and deletions (HS indels, with lengths <100 bp) are reported to be ubiquitous in the human genome. However, whether these indels contribute to human-specific traits remains unclear. Here we employ a modified McDonald-Kreitman (MK) test and a combinatorial population genetics approach to infer, respectively, the occurrence of positive selection and recent selective sweep events associated with HS indels. We first extract 625,890 HS indels from the human-chimpanzee-macaque-mouse multiple alignments and classify them into nonpolymorphic (41%) and polymorphic (59%) indels with reference to the human indel polymorphism data. The modified MK test is then applied to 100-kb partially overlapped sliding windows across the human genome to scan for the signs of positive selection. After excluding the possibility of biased gene conversion and controlling for false discovery rate, we show that HS indels are potentially positively selected in about 10 Mb of the human genome. Furthermore, the indel-associated positively selected regions overlap with genes more often than expected. However, our result suggests that the potential targets of positive selection are located in noncoding regions. Meanwhile, we also demonstrate that the genomic regions surrounding HS indels are more frequently involved in recent selective sweep than the other regions. In addition, HS indels are associated with distinct recent selective sweep events in different human subpopulations. Our results suggest that HS indels may have been associated with human adaptive changes at both the species level and the subpopulation level.