A genome-wide screen for noncoding elements important in primate evolution

<p>Abstract</p> <p>Background</p> <p>A major goal in the study of human evolution is to identify key genetic changes which occurred over the course of primate evolution. According to one school of thought, many such changes are likely to be found in noncoding sequence. An approach to identifying these involves comparing multiple genomes to identify conserved regions with an accelerated substitution rate in a particular lineage. Such acceleration could be the result of positive selection.</p> <p>Results</p> <p>Here we develop a likelihood ratio test method to identify such regions. We apply it not only to the human terminal lineage, as has been done in previous studies, but also to a number of other branches in the primate tree. We present the top scoring elements, and compare our results with previous studies. We also present resequencing data from one particular element accelerated on the human lineage. These data indicate that the element lies in a region of low polymorphism in humans, consistent with the possibility of a recent selective sweep. They also show that the AT to GC bias for polymorphism in this region differs dramatically from that for substitutions.</p> <p>Conclusion</p> <p>Our results suggest that screens of this type will be helpful in unraveling the complex set of changes which occurred during primate evolution.</p

Selective Constraint on Noncoding Regions of Hominid Genomes

An important challenge for human evolutionary biology is to understand the genetic basis of human–chimpanzee differences. One influential idea holds that such differences depend, to a large extent, on adaptive changes in gene expression. An important step in assessing this hypothesis involves gaining a better understanding of selective constraint on noncoding regions of hominid genomes. In noncoding sequence, functional elements are frequently small and can be separated by large nonfunctional regions. For this reason, constraint in hominid genomes is likely to be patchy. Here we use conservation in more distantly related mammals and amniotes as a way of identifying small sequence windows that are likely to be functional. We find that putatively functional noncoding elements defined in this manner are subject to significant selective constraint in hominids.</p

The Evolution of Word Composition in Metazoan Promoter Sequence

The field of molecular evolution provides many examples of the principle that molecular differences between species contain information about evolutionary history. One surprising case can be found in the frequency of short words in DNA: more closely related species have more similar word compositions. Interest in this has often focused on its utility in deducing phylogenetic relationships. However, it is also of interest because of the opportunity it provides for studying the evolution of genome function. Word-frequency differences between species change too slowly to be purely the result of random mutational drift. Rather, their slow pattern of change reflects the direct or indirect action of purifying selection and the presence of functional constraints. Many such constraints are likely to exist, and an important challenge is to distinguish them. Here we develop a method to do so by isolating the effects acting at different word sizes. We apply our method to 2-, 4-, and 8-base-pair (bp) words across several classes of noncoding sequence. Our major result is that similarities in 8-bp word frequencies scale with evolutionary time for regions immediately upstream of genes. This association is present although weaker in intronic sequence, but cannot be detected in intergenic sequence using our method. In contrast, 2-bp and 4-bp word frequencies scale with time in all classes of noncoding sequence. These results suggest that different genomic processes are involved at different word sizes. The pattern in 2-bp and 4-bp words may be due to evolutionary changes in processes such as DNA replication and repair, as has been suggested before. The pattern in 8-bp words may reflect evolutionary changes in gene-regulatory machinery, such as changes in the frequencies of transcription-factor binding sites, or in the affinity of transcription factors for particular sequences.</p

Evolution and Scaling in Mammalian Brains

Here I look at three stages in the evolutionary development of mammalian brains. Chapter one addresses how connectivity in neocortex scales with brain size. This is of evolutionary interest because it helps define the basic mammalian condition. Neocortical white matter increases disproportionately in large brains. This might reflect increases in the number of connections per neuron. It might also reflect scaling in axon diameter. I compare these hypotheses by examining white matter-gray matter scaling in cerebellum. Because the white matter of cerebellum lacks cortico-cortical connections, the connectivity theory predicts that cerebellar white matter should not hyperscale relative to gray matter. I have measured white matter and gray matter volume in a large sample of mammals and I find that cerebellar white matter does not hyperscale. This supports the proposition that neocortical hyperscaling reflects an increase in the number of connections per neuron in large brains. In chapter two I use independent contrasts analysis to examine the scaling of frontal cortex in a large sample of mammals. I find significant differences in scaling between primates and carnivores. Primate frontal cortex hyperscales relative to the rest of neocortex and the rest of the brain, and the primate slope is significantly greater than that for carnivores. This suggests that there are substantial differences in frontal cortex structure and development between the two groups. Combined with with anatomical differences, it suggests that primates have evolved a number of unique adaptations in frontal cortex. Chapter three examines the evolution of brain size in anthropoid primates. Living anthropoids have larger brains than strepsirrhines. What about early anthropoid fossils? I measure brain size in the early anthropoid Parapithecus grangeri using computed tomography. I find that relative to the living anthropoids, Parapithecus had a small brain for its body size. Thus large brains did not develop at the same time as a number of other anthropoid adaptations.</p

Context dependent substitution biases vary within the human genome

Background: Models of sequence evolution typically assume that different nucleotide positions evolve independently. This assumption is widely appreciated to be an over-simplification. The best known violations involve biases due to adjacent nucleotides. There have also been suggestions that biases exist at larger scales, however this possibility has not been systematically explored. Results: To address this we have developed a method which identifies over- and under-represented substitution patterns and assesses their overall impact on the evolution of genome composition. Our method is designed to account for biases at smaller pattern sizes, removing their effects. We used this method to investigate context bias in the human lineage after the divergence from chimpanzee. We examined bias effects in substitution patterns between 2 and 5 bp long and found significant effects at all sizes. This included some individual three and four base pair patterns with relatively large biases. We also found that bias effects vary across the genome, differing between transposons and non-transposons, between different classes of transposons, and also near and far from genes. Conclusions: We found that nucleotides beyond the immediately adjacent one are responsible for substantial context effects, and that these biases vary across the genome

Different classes of tissue-specific genes show different levels of noncoding conservation

AbstractWe divide tissue-specific genes into two major classes: regulators, defined as genes participating in tissue-specific transcriptional regulation, and effectors, defined as genes involved in rendering the physiological properties of cells. We show that regulators tend to have significantly greater noncoding conservation than effectors. We further show that within the regulator class, tissue-specific transcription factors generally have the greatest noncoding conservation, whereas signal receptors generally have the least noncoding conservation. Using noncoding conservation as a proxy for the complexity of cis-regulatory DNA, we extrapolate that different classes of tissue-specific genes tend to have different levels of cis-regulatory complexity and that greater complexity can be found in genes involved in transcriptional regulation, especially transcription factors

Selective Constraint on Noncoding Regions of Hominid Genomes

An important challenge for human evolutionary biology is to understand the genetic basis of human–chimpanzee differences. One influential idea holds that such differences depend, to a large extent, on adaptive changes in gene expression. An important step in assessing this hypothesis involves gaining a better understanding of selective constraint on noncoding regions of hominid genomes. In noncoding sequence, functional elements are frequently small and can be separated by large nonfunctional regions. For this reason, constraint in hominid genomes is likely to be patchy. Here we use conservation in more distantly related mammals and amniotes as a way of identifying small sequence windows that are likely to be functional. We find that putatively functional noncoding elements defined in this manner are subject to significant selective constraint in hominids

The Evolution of Word Composition in Metazoan Promoter Sequence

The field of molecular evolution provides many examples of the principle that molecular differences between species contain information about evolutionary history. One surprising case can be found in the frequency of short words in DNA: more closely related species have more similar word compositions. Interest in this has often focused on its utility in deducing phylogenetic relationships. However, it is also of interest because of the opportunity it provides for studying the evolution of genome function. Word-frequency differences between species change too slowly to be purely the result of random mutational drift. Rather, their slow pattern of change reflects the direct or indirect action of purifying selection and the presence of functional constraints. Many such constraints are likely to exist, and an important challenge is to distinguish them. Here we develop a method to do so by isolating the effects acting at different word sizes. We apply our method to 2-, 4-, and 8-base-pair (bp) words across several classes of noncoding sequence. Our major result is that similarities in 8-bp word frequencies scale with evolutionary time for regions immediately upstream of genes. This association is present although weaker in intronic sequence, but cannot be detected in intergenic sequence using our method. In contrast, 2-bp and 4-bp word frequencies scale with time in all classes of noncoding sequence. These results suggest that different genomic processes are involved at different word sizes. The pattern in 2-bp and 4-bp words may be due to evolutionary changes in processes such as DNA replication and repair, as has been suggested before. The pattern in 8-bp words may reflect evolutionary changes in gene-regulatory machinery, such as changes in the frequencies of transcription-factor binding sites, or in the affinity of transcription factors for particular sequences