Courtney C. Babbitt

Convergent adaptation of human lactase persistence in Africa and Europe

A SNP in the gene encoding lactase (LCT) (C/T-13910) is associated with the ability to digest milk as adults (lactase persistence) in Europeans, but the genetic basis of lactase persistence in Africans was previously unknown. We conducted a genotype-phenotype association study in 470 Tanzanians, Kenyans and Sudanese and identified three SNPs (G/C-14010, T/G-13915 and C/G-13907) that are associated with lactase persistence and that have derived alleles that significantly enhance transcription from the LCT promoter in vitro. These SNPs originated on different haplotype backgrounds from the European C/T-13910 SNP and from each other. Genotyping across a 3-Mb region demonstrated haplotype homozygosity extending >2.0 Mb on chromosomes carrying C-14010, consistent with a selective sweep over the past ∼7,000 years. These data provide a marked example of convergent evolution due to strong selective pressure resulting from shared cultural traits—animal domestication and adult milk consumption.

Population Genomics Reveal Recent Speciation and Rapid Evolutionary Adaptation in Polar Bears

Polar bears are uniquely adapted to life in the High Arctic and have undergone drastic physiological changes in response to Arctic climates and a hyper-lipid diet of primarily marine mammal prey. We analyzed 89 complete genomes of polar bear and brown bear using population genomic modeling and show that the species diverged only 479-343 thousand years BP. We find that genes on the polar bear lineage have been under stronger positive selection than in brown bears; nine of the top 16 genes under strong positive selection are associated with cardiomyopathy and vascular disease, implying important reorganization of the cardiovascular system. One of the genes showing the strongest evidence of selection, APOB, encodes the primary lipoprotein component of low-density lipoprotein (LDL); functional mutations in APOB may explain how polar bears are able to cope with life-long elevated LDL levels that are associated with high risk of heart disease in humans.

Both Noncoding and Protein-Coding RNAs Contribute to Gene Expression Evolution in the Primate Brain

Despite striking differences in cognition and behavior between humans and our closest primate relatives, several studies have found little evidence for adaptive change in protein-coding regions of genes expressed primarily in the brain. Instead, changes in gene expression may underlie many cognitive and behavioral differences. Here, we used digital gene expression: tag profiling (here called Tag-Seq, also called DGE:tag profiling) to assess changes in global transcript abundance in the frontal cortex of the brains of 3 humans, 3 chimpanzees, and 3 rhesus macaques. A substantial fraction of transcripts we identified as differentially transcribed among species were not assayed in previous studies based on microarrays. Differentially expressed tags within coding regions are enriched for gene functions involved in synaptic transmission, transport, oxidative phosphorylation, and lipid metabolism. Importantly, because Tag-Seq technology provides strand-specific information about all polyadenlyated transcripts, we were able to assay expression in noncoding intragenic regions, including both sense and antisense noncoding transcripts (relative to nearby genes). We find that many noncoding transcripts are conserved in both location and expression level between species, suggesting a possible functional role. Lastly, we examined the overlap between differential gene expression and signatures of positive selection within putative promoter regions, a sign that these differences represent adaptations during human evolution. Comparative approaches may provide important insights into genes responsible for differences in cognitive functions between humans and nonhuman primates, as well as highlighting new candidate genes for studies investigating neurological disorders.

Extensive evolutionary changes in regulatory element activity during human origins are associated with altered gene expression and positive selection.

Understanding the molecular basis for phenotypic differences between humans and other primates remains an outstanding challenge. Mutations in non-coding regulatory DNA that alter gene expression have been hypothesized as a key driver of these phenotypic differences. This has been supported by differential gene expression analyses in general, but not by the identification of specific regulatory elements responsible for changes in transcription and phenotype. To identify the genetic source of regulatory differences, we mapped DNaseI hypersensitive (DHS) sites, which mark all types of active gene regulatory elements, genome-wide in the same cell type isolated from human, chimpanzee, and macaque. Most DHS sites were conserved among all three species, as expected based on their central role in regulating transcription. However, we found evidence that several hundred DHS sites were gained or lost on the lineages leading to modern human and chimpanzee. Species-specific DHS site gains are enriched near differentially expressed genes, are positively correlated with increased transcription, show evidence of branch-specific positive selection, and overlap with active chromatin marks. Species-specific sequence differences in transcription factor motifs found within these DHS sites are linked with species-specific changes in chromatin accessibility. Together, these indicate that the regulatory elements identified here are genetic contributors to transcriptional and phenotypic differences among primate species.

Contrasts between adaptive coding and noncoding changes during human evolution

Changes in non–protein-coding regulatory DNA sequences have been proposed to play distinctive roles in adaptive evolution. We analyzed correlations between gene functions and evidence for positive selection in a common statistical framework across several large surveys of coding and noncoding sequences throughout the human genome. Strong correlations with both classifications in gene ontologies and measurements of gene expression indicate that neural development and function have adapted mainly through noncoding changes. In contrast, adaptation via coding changes is dominated by immunity, olfaction, and male reproduction. Genes with highly tissue-specific expression have undergone more adaptive coding changes, suggesting that pleiotropic constraints inhibit such changes in broadly expressed genes. In contrast, adaptive noncoding changes do not exhibit this pattern. Our findings underscore the probable importance of noncoding changes in the evolution of human traits, particularly cognitive traits.

Genetics of gene expression responses to temperature stress in a sea urchin gene network

Stress responses play an important role in shaping species distributions and robustness to climate change. We investigated how stress responses alter the contribution of additive genetic variation to gene expression during development of the purple sea urchin, Strongylocentrotus purpuratus, under increased temperatures that model realistic climate change scenarios. We first measured gene expression responses in the embryos by RNA‐seq to characterize molecular signatures of mild, chronic temperature stress in an unbiased manner. We found that an increase from 12 to 18 °C caused widespread alterations in gene expression including in genes involved in protein folding, RNA processing and development. To understand the quantitative genetic architecture of this response, we then focused on a well‐characterized gene network involved in endomesoderm and ectoderm specification. Using a breeding design with wild‐caught individuals, we measured genetic and gene–environment interaction effects on 72 genes within this network. We found genetic or maternal effects in 33 of these genes and that the genetic effects were correlated in the network. Fourteen network genes also responded to higher temperatures, but we found no significant genotype–environment interactions in any of the genes. This absence may be owing to an effective buffering of the temperature perturbations within the network. In support of this hypothesis, perturbations to regulatory genes did not affect the expression of the genes that they regulate. Together, these results provide novel insights into the relationship between environmental change and developmental evolution and suggest that climate change may not expose large amounts of cryptic genetic variation to selection in this species.

The Impact of Gene Expression Variation on the Robustness and Evolvability of a Developmental Gene Regulatory Network

Changes in the nature of gene interactions during development help explain the robustness of early development and the basis for developmental evolution.

Genomic signatures of diet-related shifts during human origins.

There are numerous anthropological analyses concerning the importance of diet during human evolution. Diet is thought to have had a profound influence on the human phenotype, and dietary differences have been hypothesized to contribute to the dramatic morphological changes seen in modern humans as compared with non-human primates. Here, we attempt to integrate the results of new genomic studies within this well-developed anthropological context. We then review the current evidence for adaptation related to diet, both at the level of sequence changes and gene expression. Finally, we propose some ways in which new technologies can help identify specific genomic adaptations that have resulted in metabolic and morphological differences between humans and non-human primates.

A Pipeline to Determine RT-QPCR Control Genes for Evolutionary Studies: Application to Primate Gene Expression across Multiple Tissues

Because many species-specific phenotypic differences are assumed to be caused by differential regulation of gene expression, many recent investigations have focused on measuring transcript abundance. Despite the availability of high-throughput platforms, quantitative real-time polymerase chain reaction (RT-QPCR) is often the method of choice because of its low cost and wider dynamic range. However, the accuracy of this technique heavily relies on the use of multiple valid control genes for normalization. We created a pipeline for choosing genes potentially useful as RT-QPCR control genes for measuring expression between human and chimpanzee samples across multiple tissues, using published microarrays and a measure of tissue-specificity. We identified 13 genes from the pipeline and from commonly used control genes: ACTB, USP49, ARGHGEF2, GSK3A, TBP, SDHA, EIF2B2, GPDH, YWHAZ, HPTR1, RPL13A, HMBS, and EEF2. We then tested these candidate genes and validated their expression stability across species. We established the rank order of the most preferable set of genes for single and combined tissues. Our results suggest that for at least three tissues (cerebral cortex, liver, and skeletal muscle), EIF2B2, EEF2, HMBS, and SDHA are useful genes for normalizing human and chimpanzee expression using RT-QPCR. Interestingly, other commonly used control genes, including TBP, GAPDH, and, especially ACTB do not perform as well. This pipeline could be easily adapted to other species for which expression data exist, providing taxonomically appropriate control genes for comparisons of gene expression among species.

A potential role for glucose transporters in the evolution of human brain size.

Differences in cognitive abilities and the relatively large brain are among the most striking differences between humans and their closest primate relatives. The energy trade-off hypothesis predicts that a major shift in energy allocation among tissues occurred during human origins in order to support the remarkable expansion of a metabolically expensive brain. However, the molecular basis of this adaptive scenario is unknown. Two glucose transporters (SLC2A1 and SLC2A4) are promising candidates and present intriguing mutations in humans, resulting, respectively, in microcephaly and disruptions in whole-body glucose homeostasis. We compared SLC2A1 and SLC2A4 expression between humans, chimpanzees and macaques, and found compensatory and biologically significant expression changes on the human lineage within cerebral cortex and skeletal muscle, consistent with mediating an energy trade-off. We also show that these two genes are likely to have undergone adaptation and participated in the development and maintenance of a larger brain in the human lineage by modulating brain and skeletal muscle energy allocation. We found that these two genes show human-specific signatures of positive selection on known regulatory elements within their 5′-untranslated region, suggesting an adaptation of their regulation during human origins. This study represents the first case where adaptive, functional and genetic lines of evidence implicate specific genes in the evolution of human brain size.