An exploration of the parallel evolution of iridescent structural colour in Heliconius butterflies

Understanding how selection interacts with genetic variation to produce biodiversity is a central theme in evolutionary biology. Many studies have taken advantage of the rich diversity of colouration in animals to tackle this, as colour is both ecologically relevant and a clearly visible phenotype. This has carried over into the ‘omics’ era, with plenty of studies addressing evolutionary questions by examining the genomics of colouration in natural populations. These studies tend to focus on discrete colour variation and pigmentation. However, most phenotypic variation is continuous, and little is known about the genetics of structural colour. Heliconius butterflies display warning colouration that boasts both striking diversity, alongside near-perfect convergence between mimetic species. Repeated evolution of pigment colour patterns is driven by the repeated use of a small set of genes. On the western slopes of the Andes, convergent iridescence has also evolved between the co-mimics Heliconius erato and Heliconius melpomene, which appears to vary continuously. In this thesis I (1) describe clinal variation in iridescence across hybrid zones between iridescent and non-iridescent subspecies of H. erato and H. melpomene and highlight a common selective agent (mimetic warning colouration), yet different migration-selection balance between the species. 2) I demonstrate a striking difference in levels of population structure between the co-mimics across their hybrid zones. However, in both species variation in iridescence is independent of population structure and is maintained by selection despite gene flow. (3) I describe the genetic architecture of iridescence in Heliconius, for the first time, using association mapping. Lack of power to estimate genetic architecture for H. melpomene prevented a thorough between-species comparison. However, I find potential evidence of overlapping genomic regions responsible for variation in iridescence. This thesis lays the groundwork for future research narrowing down the genetic underpinnings of iridescence in this system

Contrasted histories of organelle and nuclear genomes underlying physiological diversification in a grass species: Intraspecific dispersal of C4 physiology

C 4 photosynthesis evolved multiple times independently in angiosperms, but most origins are relatively old so that the early events linked to photosynthetic diversification are blurred. The grass Alloteropsis semialata is an exception, as this species encompasses C 4 and non-C 4 populations. Using phylogenomics and population genomics, we infer the history of dispersal and secondary gene flow before, during and after photosynthetic divergence in A. semialata. We further analyse the genome composition of individuals with varied ploidy levels to establish the origins of polyploids in this species. Detailed organelle phylogenies indicate limited seed dispersal within the mountainous region of origin and the emergence of a C 4 lineage after dispersal to warmer areas of lower elevation. Nuclear genome analyses highlight repeated secondary gene flow. In particular, the nuclear genome associated with the C 4 phenotype was swept into a distantly related maternal lineage probably via unidirectional pollen flow. Multiple intraspecific allopolyploidy events mediated additional secondary genetic exchanges between photosynthetic types. Overall, our results show that limited dispersal and isolation allowed lineage divergence, with photosynthetic innovation happening after migration to new environments, and pollen-mediated gene flow led to the rapid spread of the derived C 4 physiology away from its region of origin.This study was funded by the European Research Council (grant no. ERC-2014-STG-638333), the Royal Society (grant no. RGF\EA\181050) and has benefited from ‘Investissements d'Avenir' grants managed by the Agence Nationale de la Recherche (CEBA, ref. ANR-10-LABX-25-01 and TULIP, ref. ANR-10-LABX-41). Edinburgh Genomics, which contributed to the sequencing, is partly supported through core grants from the NERC (grant no. R8/H10/ 56), MRC (grant no. MR/K001744/1) and BBSRC (grant no. BB/ J004243/1). P.A.C. is funded by a Royal Society University Research Fellowship (grant no. URF\R\180022).Abstract 1. Introduction 2. Materials and methods (a) Sampling, sequencing and data filtering (b) Genome sizing and carbon isotope analyses (c) Assembly of organelle genomes and molecular dating (d) Phylogenetic analyses of the nuclear genome (e) Genetic structure (f) Genome composition 3. Results (a) Genome sizes (b) Time-calibrated organelle phylogenies (c) Nuclear phylogeny (d) Population structure and genome composition 4. Discussion (a) Limited seed dispersal in the region of origin (b) Widespread pollen flow and sweep of the C4 nuclear genome (c) Recurrent hybridization and polyploidization 5. Concluding remarks Data accessibility Authors' contributions Competing interests Funding Acknowledgements Footnote

Genetic Overlap Profiles of Cognitive Ability in Psychotic and Affective Illnesses::A Multi-Site Study of Multiplex Pedigrees

BACKGROUND: Cognitive impairment is a key feature of psychiatric illness, making cognition an important tool for exploring of the genetics of illness risk. It remains unclear which measures should be prioritized in pleiotropy-guided research. Here, we generate profiles of genetic overlap between psychotic and affective disorders and cognitive measures in Caucasian and Hispanic groups. METHODS: Data were from four samples of extended pedigrees (N = 3046). Coefficient of relationship analyses were used to estimate genetic overlap between illness risk and cognitive ability. Results were meta-analyzed. FINDINGS: Psychosis was characterized by cognitive impairments on all measures with a generalized profile of genetic overlap. General cognitive ability shared greatest genetic overlap with psychosis risk (average Endophenotype Ranking Value (ERV) across samples from a random-effects meta-analysis = 0.32) followed by Verbal Memory (ERV = 0.24), Executive Function (ERV = 0.22), and Working Memory (ERV = 0.21). For bipolar disorder, there was genetic overlap with Processing Speed (ERV = 0.05) and Verbal Memory (ERV = 0.11), but these were confined to select samples. Major depression was characterized by enhanced Working and Face Memory performance, as reflected in significant genetic overlap in two samples. INTERPRETATION: There is substantial genetic overlap between risk for psychosis and a range of cognitive abilities (including general intelligence). Most of these effects are largely stable across of ascertainment strategy and ethnicity. Genetic overlap between affective disorders and cognition, on the other hand, tend to be specific to ascertainment strategy, ethnicity, and cognitive test battery

Multi-site genetic analysis of diffusion images and voxelwise heritability analysis : a pilot project of the ENIGMA–DTI working group

The ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) Consortium was set up to analyze brain measures and genotypes from multiple sites across the world to improve the power to detect genetic variants that influence the brain. Diffusion tensor imaging (DTI) yields quantitative measures sensitive to brain development and degeneration, and some common genetic variants may be associated with white matter integrity or connectivity. DTI measures, such as the fractional anisotropy (FA) of water diffusion, may be useful for identifying genetic variants that influence brain microstructure. However, genome-wide association studies (GWAS) require large populations to obtain sufficient power to detect and replicate significant effects, motivating a multi-site consortium effort. As part of an ENIGMA–DTI working group, we analyzed high-resolution FA images from multiple imaging sites across North America, Australia, and Europe, to address the challenge of harmonizing imaging data collected at multiple sites. Four hundred images of healthy adults aged 18–85 from four sites were used to create a template and corresponding skeletonized FA image as a common reference space. Using twin and pedigree samples of different ethnicities, we used our common template to evaluate the heritability of tract-derived FA measures. We show that our template is reliable for integrating multiple datasets by combining results through meta-analysis and unifying the data through exploratory mega-analyses. Our results may help prioritize regions of the FA map that are consistently influenced by additive genetic factors for future genetic discovery studies. Protocols and templates are publicly available at (http://enigma.loni.ucla.edu/ongoing/dti-working-group/)

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

The impact of immediate breast reconstruction on the time to delivery of adjuvant therapy: the iBRA-2 study

Background: Immediate breast reconstruction (IBR) is routinely offered to improve quality-of-life for women requiring mastectomy, but there are concerns that more complex surgery may delay adjuvant oncological treatments and compromise long-term outcomes. High-quality evidence is lacking. The iBRA-2 study aimed to investigate the impact of IBR on time to adjuvant therapy. Methods: Consecutive women undergoing mastectomy ± IBR for breast cancer July–December, 2016 were included. Patient demographics, operative, oncological and complication data were collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR were compared and risk factors associated with delays explored. Results: A total of 2540 patients were recruited from 76 centres; 1008 (39.7%) underwent IBR (implant-only [n = 675, 26.6%]; pedicled flaps [n = 105,4.1%] and free-flaps [n = 228, 8.9%]). Complications requiring re-admission or re-operation were significantly more common in patients undergoing IBR than those receiving mastectomy. Adjuvant chemotherapy or radiotherapy was required by 1235 (48.6%) patients. No clinically significant differences were seen in time to adjuvant therapy between patient groups but major complications irrespective of surgery received were significantly associated with treatment delays. Conclusions: IBR does not result in clinically significant delays to adjuvant therapy, but post-operative complications are associated with treatment delays. Strategies to minimise complications, including careful patient selection, are required to improve outcomes for patients

Novel genetic loci underlying human intracranial volume identified through genome-wide association

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five novel loci for intracranial volume and confirmed two known signals. Four of the loci are also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic=0.748), which indicated a similar genetic background and allowed for the identification of four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, Parkinson’s disease, and enriched near genes involved in growth pathways including PI3K–AKT signaling. These findings identify biological underpinnings of intracranial volume and provide genetic support for theories on brain reserve and brain overgrowth

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder