Genome sequences from North American Drosophila melanogaster populations have become available to the scientific community. Deciphering the underlying population structure of these resources is crucial to make the most of these population genomic resources. Accepted models of North American colonization generally purport that several hundred years ago, flies from Africa and Europe were transported to the east coast United States and the Caribbean Islands respectively and thus current east coast US and Caribbean populations are an admixture of African and European ancestry. Theses models have been constructed based on phenotypes and limited genetic data. In our study, we have sequenced individual whole genomes of flies from populations in the southeast US and Caribbean Islands and examined these populations in conjunction with population sequences from Winters, CA, (USA); Raleigh, NC (USA); Cameroon (Africa); and Montpellier (France) to uncover the underlying population structure of North American populations. We find that west coast US populations are most like European populations likely reflecting a rapid westward expansion upon first settlements into North America. We also find genomic evidence of African and European admixture in east coast US and Caribbean populations, with a clinal pattern of decreasing proportions of African ancestry with higher latitude further supporting the proposed demographic model of Caribbean flies being established by African ancestors. Our genomic analysis of Caribbean flies is the first study that exposes the source of previously reported novel African alleles found in east coast US populations.

Drosophila melanogaster is postulated to have colonized North America in the past several 100 years in two waves. Flies from Europe colonized the east coast United States while flies from Africa inhabited the Caribbean, which if true, make the south-east US and Caribbean Islands a secondary contact zone for African and European D. melanogaster. This scenario has been proposed based on phenotypes and limited genetic data. In our study, we have sequenced individual whole genomes of flies from populations in the south-east US and Caribbean Islands and examined these populations in conjunction with population sequences from the west coast US, Africa, and Europe. We find that west coast US populations are closely related to the European population, likely reflecting a rapid westward expansion upon first settlements into North America. We also find genomic evidence of African and European admixture in south-east US and Caribbean populations, with a clinal pattern of decreasing proportions of African ancestry with higher latitude. Our genomic analysis of D. melanogaster populations from the south-east US and Caribbean Islands provides more evidence for the Caribbean Islands as the source of previously reported novel African alleles found in other east coast US populations. We also find the border between the south-east US and the Caribbean island to be the admixture hot zone where distinctly African-like Caribbean flies become genomically more similar to European-like south-east US flies. Our findings have important implications for previous studies examining the generation of east coast US clines via selection.

The power of genome-wide association studies (GWAS) rests on several foundations: (i) there is a significant amount of additive genetic variation, (ii) individual causal polymorphisms often have sizable effects and (iii) they segregate at moderate-tointermediate frequencies, or will be effectively 'tagged' by polymorphisms that do. Each of these assumptions has recently been questioned. (i) Why should genetic variation appear additive given that the underlying molecular networks are highly nonlinear? (ii) A new generation of relatedness-based analyses directs us back to the nearly infinitesimal model for effect sizes that quantitative genetics was long based upon. (iii) Larger effect causal polymorphisms are often low frequency, as selection might lead us to expect. Here, we review these issues and other findings that appear to question many of the foundations of the optimism GWAS prompted. We then present a roadmap emerging as one possible future for quantitative genetics. We argue that in future GWAS should move beyond purely statistical grounds. One promising approach is to build upon the combination of population genetic models and molecular biological knowledge. This combined treatment, however, requires fitting experimental data to models that are very complex, as well as accurate capturing of the uncertainty of resulting inference. This problem can be resolved through Bayesian analysis and tools such as approximate Bayesian computation-a method growing in popularity in population genetic analysis. We show a case example of anterior-posterior segmentation in Drosophila, and argue that similar approaches will be helpful as a GWAS augmentation, in human and agricultural research.

Genomic transposable elements (TEs) comprise nearly half of the human genome. The expression of TEs is considered potentially hazardous, as it can lead to insertional mutagenesis and genomic instability. However, recent studies have revealed that TEs are involved in immune-mediated cell clearance. Hypomethylating agents can increase the expression of TEs in cancer cells, inducing ‘viral mimicry’, causing interferon signalling and cancer cell killing. To investigate the role of TEs in the pathogenesis of acute myeloid leukaemia (AML), we studied TE expression in several cell fractions of AML while tracking its development (pre-leukemic haematopoietic stem cells, leukemic stem cells [LSCs], and leukemic blasts). LSCs, which are resistant to chemotherapy and serve as reservoirs for relapse, showed significant suppression of TEs and interferon pathways. Similarly, high-risk cases of myelodysplastic syndrome (MDS) showed far greater suppression of TEs than low-risk cases. We propose TE suppression as a mechanism for immune escape in AML and MDS. Repression of TEs co-occurred with the upregulation of several genes known to modulate TE expression, such as RNA helicases and autophagy genes. Thus, we have identified potential pathways that can be targeted to activate cancer immunogenicity via TEs in AML and MDS.