Meiotic chromosome axis remodelling is critical for meiotic recombination in Brassica rapa

Meiosis generates genetic variation through homologous recombination (HR) that is harnessed during breeding. HR occurs in the context of meiotic chromosome axes and the synaptonemal complex. To study the role of axis remodelling on crossover (CO) formation in a crop species, we characterized mutants of the axis-associated protein ASY1 and the axis-remodelling protein PCH2 in Brassica rapa. asy1 plants form meiotic chromosome axes that fail to synapse. CO formation is almost abolished and residual chiasmata are proportionally enriched in terminal chromosome regions, particularly in the nucleolar organizing region (NOR)-carrying chromosome arm. pch2 plants show impaired ASY1 loading and remodelling consequently achieving only partial synapsis, which leads to reduced CO formation and loss of the obligatory CO. PCH2-independent chiasmata are proportionally enriched towards distal chromosome regions. Similarly, in Arabidopsis pch2 COs are increased towards telomeric regions at the expense of (peri-)centromeric COs compared to WT. Together, in B. rapa axis formation and remodelling are critical for meiotic fidelity including synapsis and CO formation and in asy1 and pch2 CO distributions are altered. While asy1 plants are sterile, pch2 plants are semi-sterile and thus PCH2 could be an interesting target for breeding programs.

Variation in Recombination Rate Is Shaped by Domestication and Environmental Conditions in Barley

Meiotic recombination generates genetic diversity upon which selection can act. Recombination rates are highly variable between species, populations, individuals, sexes, chromosomes, and chromosomal regions. The underlying mechanisms are controlled at the genetic and epigenetic level and show plasticity toward the environment. Environmental plasticity may be divided into short- and long-term responses. We estimated recombination rates in natural populations of wild barley and domesticated landraces using a population genetics approach. We analyzed recombination landscapes in wild barley and domesticated landraces at high resolution. In wild barley, high recombination rates are found in more interstitial chromosome regions in contrast to distal chromosome regions in domesticated barley. Among subpopulations of wild barley, natural variation in effective recombination rate is correlated with temperature, isothermality, and solar radiation in a nonlinear manner. A positive linear correlation was found between effective recombination rate and annual precipitation. We discuss our findings with respect to how the environment might shape effective recombination rates in natural populations. Higher recombination rates in wild barley populations subjected to specific environmental conditions could be a means to maintain fitness in a strictly inbreeding species.

Distal chromosome 16p11.2 duplications containing SH2B1 in patients with scoliosis

IntroductionAdolescent idiopathic scoliosis (AIS) is a common musculoskeletal disorder with strong evidence for a genetic contribution. CNVs play an important role in congenital scoliosis, but their role in idiopathic scoliosis has been largely unexplored.MethodsExome sequence data from 1197 AIS cases and 1664 in-house controls was analysed using coverage data to identify rare CNVs. CNV calls were filtered to include only highly confident CNVs with >10 average reads per region and mean log-ratio of coverage consistent with single-copy duplication or deletion. The frequency of 55 common recurrent CNVs was determined and correlated with clinical characteristics.ResultsDistal chromosome 16p11.2 microduplications containing the gene SH2B1 were found in 0.7% of AIS cases (8/1197). We replicated this finding in two additional AIS cohorts (8/1097 and 2/433), resulting in 0.7% (18/2727) of all AIS cases harbouring a chromosome 16p11.2 microduplication, compared with 0.06% of local controls (1/1664) and 0.04% of published controls (8/19584) (p=2.28×10−11, OR=16.15). Furthermore, examination of electronic health records of 92 455 patients from the Geisinger health system showed scoliosis in 30% (20/66) patients with chromosome 16p11.2 microduplications containing SH2B1 compared with 7.6% (10/132) of controls (p=5.6×10−4, OR=3.9).ConclusionsRecurrent distal chromosome 16p11.2 duplications explain nearly 1% of AIS. Distal chromosome 16p11.2 duplications may contribute to scoliosis pathogenesis by directly impairing growth or by altering expression of nearby genes, such as TBX6. Individuals with distal chromosome 16p11.2 microduplications should be screened for scoliosis to facilitate early treatment.

Distal 22q11.2 Microduplication

Distal chromosome 22q11.2 microduplications are associated with a wide range of phenotypes and unclear pathogenicity. The authors report on a 3-year-old girl with global developmental delay harboring a de novo 1.24 Mb distal chromosome 22q11.2 microduplication and a paternally inherited 0.25 Mb chromosome 4p14 microduplication. The authors review clinical features of 30 reported cases of distal 22q11.2 duplications. Common features include developmental delay (93%), neuropsychiatric features (26%), and nonspecific facial dysmorphisms (74%). In 70% of cases, the distal 22q11.2 duplications were inherited, and the majority of the carrier parents were phenotypically normal. Furthermore, 30% of probands carried an additional copy number variant. Review of the phenotype in individuals carrying microduplications involving similar low copy repeats (LCR) failed to establish any clear genotype–phenotype correlations. Distal 22q11.2 duplications represent a major challenge for genetic counseling and prediction of clinical consequences. Our report suggests a pathogenic role of distal 22q11.2 duplications and supports a “multiple hit” hypothesis underlying its variable expressivity and phenotypic severity.