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Open Access Publications from the University of California

Scholarly Works (86 results)

  • Article
  • Peer Reviewed
UCLA Previously Published Works (2009)
Genetic approaches to dissecting complex traits in animal models increasingly use transcript levels as a molecular phenotype and as validation for predictions of gene function. A recent study in BMC Biology using these approaches shows the complexity of the genetic contribution to aggressive behavior in Drosophila.
    Cover page: The complex genetic basis of simple behavior
    • Article
    • Peer Reviewed
    UCLA Previously Published Works (2019)
    Internet-connected devices could transform our understanding of the causes of behavioural variation and its impact on health and disease, in particular for neuropsychiatric disorders.
      Cover page: Integrating behavioural health tracking in human genetics research
      • Thesis
      • Peer Reviewed
      UCLA Electronic Theses and Dissertations (2018)

      Bipolar disorder (BD) is a highly heritable mood disorder with a complex genetic architecture. It is commonly treated prophylactically with the mood stabilizer lithium, although treatment responses vary widely across patients. Both how BD genetic variants confer risk and the molecular mechanisms underlying lithium’s therapeutic effects remain poorly understood. This dissertation begins with a review of recent findings from BD and lithium-response genetic studies and from BD and lithium treatment transcriptomic studies. This review will show that while presenting an opportunity to learn valuable information about underlying biology, gene expression studies investigating these phenotypes have had low sample sizes and inconsistent findings. Then, an original study attempting to fill this gap by exploring the whole blood transcriptome in a large BD case-control RNA sequencing sample is reported on. In this study, strong effects of lithium treatment and cell-type composition were revealed, pointing to potential therapeutic mechanisms of lithium, and underlining the importance of carefully correcting for these variables. To put these findings in the context of the current understanding of BD etiology and lithium treatment mechanisms, a comparison was made with findings previously reported highlighting a list of high-confidence lithium-associated genes. A gene-set analysis comparing genes with differential expression to genes implicated from major psychiatric genome-wide association studies revealed that the observed gene expression changes were unrelated to genetic risk. The findings herein contribute to the current understanding of the BD transcriptome in whole blood and provide evidence for the mechanistic actions of lithium treatment.

        Cover page: The molecular signatures of bipolar disorder and lithium treatment
        • Article
        • Peer Reviewed
        UCLA Previously Published Works (2004)
        Recent studies have identified a small number of genomic rearrangements that occur frequently in the general population. Bioinformatics tools are now available for systematic genome-wide surveys of higher-order structures predisposing to such common variations in genomic architecture. Segmental duplications (SDs) constitute up to 5 per cent of the genome and play an important role in generating additional rearrangements and in disease aetiology. We conducted a genome-wide database search for a form of SD, palindromic segmental duplications (PSDs), which consist of paired, inverted duplications, and which predispose to inversions, duplications and deletions. The survey was complemented by a search for SDs in tandem orientation (TSDs) that can mediate duplications and deletions but not inversions. We found more than 230 distinct loci with higher-order genomic structure that can mediate genomic variation, of these about 180 contained a PSD. A number of these sites were previously identified as harbouring common inversions or as being associated with specific genomic diseases characterised by duplication, deletions or inversions. Most of the regions, however, were previously unidentified; their characterisation should identify further common rearrangements and may indicate localisations for additional genomic disorders. The widespread distribution of complex chromosomal architecture suggests a potentially high degree of plasticity of the human genome and could uncover another level of genetic variation within human populations.
          Cover page: A genome-wide survey of segmental duplications that mediate common human genetic variation of chromosomal architecture
          • Article
          • Peer Reviewed
          Abstract Recent studies have identified a small number of genomic rearrangements that occur frequently in the general population. Bioinformatics tools are now available for systematic genome-wide surveys of higher-order structures predisposing to such common variations in genomic architecture. Segmental duplications (SDs) constitute up to 5 per cent of the genome and play an important role in generating additional rearrangements and in disease aetiology. We conducted a genome-wide database search for a form of SD, palindromic segmental duplications (PSDs), which consist of paired, inverted duplications, and which predispose to inversions, duplications and deletions. The survey was complemented by a search for SDs in tandem orientation (TSDs) that can mediate duplications and deletions but not inversions. We found more than 230 distinct loci with higher-order genomic structure that can mediate genomic variation, of these about 180 contained a PSD. A number of these sites were previously identified as harbouring common inversions or as being associated with specific genomic diseases characterised by duplication, deletions or inversions. Most of the regions, however, were previously unidentified; their characterisation should identify further common rearrangements and may indicate localisations for additional genomic disorders. The widespread distribution of complex chromosomal architecture suggests a potentially high degree of plasticity of the human genome and could uncover another level of genetic variation within human populations.
            Cover page: A genome-wide survey of segmental duplications that mediate common human genetic variation of chromosomal architecture
            • Article
            • Peer Reviewed
            UCLA Previously Published Works (2017)
            The northern elephant seal, Mirounga angustirostris, was heavily hunted and declared extinct in the 19th century. However, a colony remained on remote Guadalupe Island, Mexico and the species has since repopulated most of its historical distribution. Here, we present a comprehensive evaluation of genetic variation in the species. First, we assess the effect of the demographic bottleneck on microsatellite variability and compare it with that found in other pinnipeds, demonstrating levels of variation similar to that in species that continue to be threatened with extinction. Next, we use sequence data from these markers to demonstrate that some of the limited polymorphism predates the bottleneck. However, most contemporary variation appears to have arisen recently and persisted due to exponential growth. We also describe how we use the range in allele size of microsatellites to estimate ancestral effective population size before the bottleneck, demonstrating a large reduction in effective size. We then employ a classical method for bacteria to estimate the microsatellite mutation rate in the species, deriving an estimate that is extremely similar to that estimated for a similar set of loci in humans, indicating consistency of microsatellite mutation rates in mammals. Finally, we find slight significant structure between some geographically separated colonies, although its biological significance is unclear. This work demonstrates that genetic analysis can be useful for evaluating the population biology of the northern elephant seal, in spite of the bottleneck that removed most genetic variation from the species.
              Cover page: Molecular Population Genetics of the Northern Elephant Seal Mirounga angustirostris.
              • Article
              • Peer Reviewed
              UCLA Previously Published Works (2018)
              OBJECTIVES:Direct comparative work in morphology and growth on widely dispersed wild primate taxa is rarely accomplished, yet critical to understanding ecogeographic variation, plastic local variation in response to human impacts, and variation in patterns of growth and sexual dimorphism. We investigated population variation in morphology and growth in response to geographic variables (i.e., latitude, altitude), climatic variables (i.e., temperature and rainfall), and human impacts in the vervet monkey (Chlorocebus spp.). METHODS:We trapped over 1,600 wild vervets from across Sub-Saharan Africa and the Caribbean, and compared measurements of body mass, body length, and relative thigh, leg, and foot length in four well-represented geographic samples: Ethiopia, Kenya, South Africa, and St. Kitts & Nevis. RESULTS:We found significant variation in body mass and length consistent with Bergmann's Rule in adult females, and in adult males when excluding the St. Kitts & Nevis population, which was more sexually dimorphic. Contrary to Rensch's Rule, although the South African population had the largest average body size, it was the least dimorphic. There was significant, although very small, variation in all limb segments in support for Allen's Rule. Females in high human impact areas were heavier than those with moderate exposures, while those in low human impact areas were lighter; human impacts had no effect on males. CONCLUSIONS:Vervet monkeys appear to have adapted to local climate as predicted by Bergmann's and, less consistently, Allen's Rule, while also responding in predicted ways to human impacts. To better understand deviations from predicted patterns will require further comparative work in vervets.
                Cover page: Morphological variation in the genus Chlorocebus: Ecogeographic and anthropogenically mediated variation in body mass, postcranial morphology, and growth.
                • Article
                • Peer Reviewed
                UCLA Previously Published Works (2015)
                Sexual traits vary tremendously in static allometry. This variation may be explained in part by body size-related differences in the strength of selection. We tested this hypothesis with in two populations of vervet monkeys, using estimates of the level of condition dependence for different morphological traits as a proxy for body size-related variation in the strength of selection. In support of the hypothesis, we found that the steepness of allometric slopes increased with the level of condition dependence. One trait of particular interest, the penis, had shallow allometric slopes and low levels of condition dependence, in agreement with one of the most consistent patterns yet detected in the study of allometry, that of genitalia exhibitting shallow allometries.
                  • Article
                  • Peer Reviewed
                  UCLA Previously Published Works (2016)

                  Objective

                  Vervet monkeys are common in most tree-rich areas of South Africa, but their absence from grassland and semi-desert areas of the country suggest potentially restricted and mosaic local population patterns that may have relevance to local phenotype patterns and selection. A portion of the mitochondrial DNA control region was sequenced to study patterns of genetic differentiation.

                  Methods

                  DNA was extracted, and mitochondrial DNA sequences were obtained from 101 vervet monkeys at 15 localities, which represent both an extensive (widely across the distribution range) and intensive (more than one troop at most of the localities) sampling strategy. Analyses utilized Arlequin 3.1, MEGA 6, BEAST v1.5.2, and Network V3.6.1.

                  Results

                  The dataset contained 26 distinct haplotypes, with six populations fixed for single haplotypes. Pairwise P-distance among population pairs showed significant differentiation among most population pairs, but with nonsignificant differences among populations within some regions. Populations were grouped into three broad clusters in a maximum likelihood phylogenetic tree and a haplotype network. These clusters correspond to i) north-western, northern, and north-eastern parts of the distribution range as well as the northern coastal belt; ii) central areas of the country; and iii) southern part of the Indian Ocean coastal belt and adjacent inland areas.

                  Conclusions

                  Apparent patterns of genetic structure correspond to current and past distribution of suitable habitat, geographic barriers to gene flow, geographic distance, and female philopatry. However, further work on nuclear markers and other genomic data are necessary to confirm these results.
                    Cover page: Localized population divergence of vervet monkeys (Chlorocebus spp.) in South Africa: Evidence from mtDNA
                    • Article
                    • Peer Reviewed
                    UCLA Previously Published Works (2019)
                    Next-generation sequencing technology (NGS) enables the discovery of nearly all genetic variants present in a genome. A subset of these variants, however, may have poor sequencing quality due to limitations in NGS or variant callers. In genetic studies that analyze a large number of sequenced individuals, it is critical to detect and remove those variants with poor quality as they may cause spurious findings. In this paper, we present ForestQC, a statistical tool for performing quality control on variants identified from NGS data by combining a traditional filtering approach and a machine learning approach. Our software uses the information on sequencing quality, such as sequencing depth, genotyping quality, and GC contents, to predict whether a particular variant is likely to be false-positive. To evaluate ForestQC, we applied it to two whole-genome sequencing datasets where one dataset consists of related individuals from families while the other consists of unrelated individuals. Results indicate that ForestQC outperforms widely used methods for performing quality control on variants such as VQSR of GATK by considerably improving the quality of variants to be included in the analysis. ForestQC is also very efficient, and hence can be applied to large sequencing datasets. We conclude that combining a machine learning algorithm trained with sequencing quality information and the filtering approach is a practical approach to perform quality control on genetic variants from sequencing data.
                      Cover page: ForestQC: Quality control on genetic variants from next-generation sequencing data using random forest
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