Variable, glutamine-encoding, CAA interruptions indicate that a property of the uninterrupted HTT CAG repeat sequence, distinct from the length of huntingtin's polyglutamine segment, dictates the rate at which Huntington's disease (HD) develops. The timing of onset shows no significant association with HTT cis-eQTLs but is influenced, sometimes in a sex-specific manner, by polymorphic variation at multiple DNA maintenance genes, suggesting that the special onset-determining property of the uninterrupted CAG repeat is a propensity for length instability that leads to its somatic expansion. Additional naturally occurring genetic modifier loci, defined by GWAS, may influence HD pathogenesis through other mechanisms. These findings have profound implications for the pathogenesis of HD and other repeat diseases and question the fundamental premise that polyglutamine length determines the rate of pathogenesis in the "polyglutamine disorders."

Determining the routes of introduction provides not only information about the history of an invasion process, but also information about the origin and construction of the genetic composition of the invading population. It remains difficult, however, to infer introduction routes from molecular data because of a lack of appropriate methods. We evaluate here the use of an approximate Bayesian computation (ABC) method for estimating the probabilities of introduction routes of invasive populations based on microsatellite data. We considered the crucial case of a single source population from which two invasive populations originated either serially from a single introduction event or from two independent introduction events. Using simulated datasets, we found that the method gave correct inferences and was robust to many erroneous beliefs. The method was also more efficient than traditional methods based on raw values of statistics such as assignment likelihood or pairwise F_ST. We illustrate some of the features of our ABC method, using real microsatellite datasets obtained for invasive populations of the western corn rootworm, Diabrotica virgifera virgifera. Most computations were performed with the DIYABC program (http://www1.montpellier.inra.fr/CBGP/diyabc/).

Huntington disease (HD) is caused by an unstable CAG/CAA repeat expansion encoding a toxic polyglutamine tract. Here, we tested the hypotheses that HD outcomes are impacted by somatic expansion of, and polymorphisms within, the HTT CAG/CAA glutamine-encoding repeat, and DNA repair genes. The sequence of the glutamine-encoding repeat and the proportion of somatic CAG expansions in blood DNA from participants inheriting 40 to 50 CAG repeats within the TRACK-HD and Enroll-HD cohorts were determined using high-throughput ultra-deep-sequencing. Candidate gene polymorphisms were genotyped using kompetitive allele-specific PCR (KASP). Genotypic associations were assessed using time-to-event and regression analyses. Using data from 203 TRACK-HD and 531 Enroll-HD participants, we show that individuals with higher blood DNA somatic CAG repeat expansion scores have worse HD outcomes: a one-unit increase in somatic expansion score was associated with a Cox hazard ratio for motor onset of 3·05 (95% CI = 1·94 to 4·80, p = 1·3 × 10^-6). We also show that individual-specific somatic expansion scores are associated with variants in FAN1 (pFDR = 4·8 × 10^-6), MLH3 (pFDR = 8·0 × 10^-4), MLH1 (pFDR = 0·004) and MSH3 (pFDR = 0·009). We also show that HD outcomes are best predicted by the number of pure CAGs rather than total encoded-glutamines. These data establish pure CAG length, rather than encoded-glutamine, as the key inherited determinant of downstream pathophysiology. These findings have implications for HD diagnostics, and support somatic expansion as a mechanistic link for genetic modifiers of clinical outcomes, a driver of disease, and potential therapeutic target in HD and related repeat expansion disorders. CHDI Foundation.

The mismatch repair gene MSH3 has been implicated as a genetic modifier of the CAG·CTG repeat expansion disorders Huntington’s disease and myotonic dystrophy type 1. A recent Huntington’s disease genome-wide association study found rs557874766, an imputed single nucleotide polymorphism located within a polymorphic 9 bp tandem repeat in MSH3/DHFR, as the variant most significantly associated with progression in Huntington’s disease. Using Illumina sequencing in Huntington’s disease and myotonic dystrophy type 1 subjects, we show that rs557874766 is an alignment artefact, the minor allele for which corresponds to a three-repeat allele in MSH3 exon 1 that is associated with a reduced rate of somatic CAG·CTG expansion (P = 0.004) and delayed disease onset (P = 0.003) in both Huntington’s disease and myotonic dystrophy type 1, and slower progression (P = 3.86 × 10⁻⁷) in Huntington’s disease. RNA-Seq of whole blood in the Huntington’s disease subjects found that repeat variants are associated with MSH3 and DHFR expression. A transcriptome-wide association study in the Huntington’s disease cohort found increased MSH3 and DHFR expression are associated with disease progression. These results suggest that variation in the MSH3 exon 1 repeat region influences somatic expansion and disease phenotype in Huntington’s disease and myotonic dystrophy type 1, and suggests a common DNA repair mechanism operates in both repeat expansion diseases.

Invasion biology and agriculture are intimately related for several reasons and in particular because many agricultural pest species are recent invaders. In this article we suggest that the reconstruction of invasion routes with population genetics-based methods can address fundamental questions in ecology and practical aspects of the management of biological invasions in agricultural settings. We provide a brief description of the methods used to reconstruct invasion routes and describe their main characteristics. In particular, we focus on a scenario – the bridgehead invasion scenario –, which had been overlooked until recently. We show that this scenario, in which an invasive population is the source of other invasive populations, is evolutionarily parsimonious and may have played a crucial role in shaping the distribution of many recent agricultural pests.