MaterialLinked-read whole genome sequencing (WGS) presents a new opportunity for cost-efficient singleton sequencing in place of traditional trio-based designs while generating informative-phased variants, effective for recessive disorders when parental DNA is unavailable.MethodsWe have applied linked-read WGS to identify novel causes of Meier-Gorlin syndrome (MGORS), a condition recognised by short stature, microtia and patella hypo/aplasia. There are eight genes associated with MGORS to date, all encoding essential components involved in establishing and initiating DNA replication.ResultsOur successful phasing of linked-read data led to the identification of biallelic rare variants in four individuals (24% of our cohort) in DONSON, a recently established DNA replication fork surveillance factor. The variants include five novel missense and one deep intronic variant. All were demonstrated to be deleterious to function; the missense variants all disrupted the nuclear localisation of DONSON, while the intronic variant created a novel splice site that generated an out-of-frame transcript with no residual canonical transcript produced.ConclusionVariants in DONSON have previously been associated with extreme microcephaly, short stature and limb anomalies and perinatal lethal microcephaly-micromelia syndrome. Our novel genetic findings extend the complicated spectrum of phenotypes associated with DONSON variants and promote novel hypotheses for the role of DONSON in DNA replication. While our findings reiterate that MGORS is a disorder of DNA replication, the pathophysiology is obviously complex. This successful identification of a novel disease gene for MGORS highlights the utility of linked-read WGS as a successful technology to be considered in the genetic studies of recessive conditions.

The MCM2-7 helicase is a heterohexameric complex with essential roles as part of both the pre-replication and pre-initiation complexes in the early stages of DNA replication. Meier-Gorlin syndrome, a rare primordial dwarfism, is strongly associated with disruption to the pre-replication complex, including a single case described with variants in MCM5. Conversely, a biallelic pathogenic variant in MCM4 underlies immune deficiency with growth retardation, features also seen in individuals with pathogenic variants in other pre-initiation complex encoding genes such as GINS1, MCM10, and POLE. Through exome and chromium genome sequencing, supported by functional studies, we identify biallelic pathogenic variants in MCM7 and a strong candidate biallelic pathogenic variant in MCM3. We confirm variants in MCM7 are deleterious and through interfering with MCM complex formation, impact efficiency of S phase progression. The associated phenotypes are striking; one patient has typical Meier-Gorlin syndrome, whereas the second case has a multi-system disorder with neonatal progeroid appearance, lipodystrophy and adrenal insufficiency. We provide further insight into the developmental complexity of disrupted MCM function, highlighted by two patients with a similar variant profile in MCM7 but disparate clinical features. Our results build on other genetic findings linked to disruption of the pre-replication and pre-initiation complexes, and the replisome, and expand the complex clinical genetics landscape emerging due to disruption of DNA replication.

We present data on the proportions and seniority of female and male political scientists working in the UK. Comparing the results with previous research from 2011, we find that progress has been made. However, progress has been incremental and we find no qualitative changes in the status of female political scientists: they continue to be outnumbered by their male counterparts; they are overrepresented in the least senior job groups and underrepresented in the most senior; and the average female political scientist occupies a less senior position than the average male counterpart. We also run regression analyses to explore the impact of broader contextual factors on the proportion of female political scientists within a unit and that unit’s ‘gender seniority gap’. We find evidence that gender equality kitemarks, university mission group membership, the gender of the Head of Unit and Vice-Chancellor and the proportion of female members of university governance bodies appear to matter for one or both of these measures but not always in the direction that might be expected. These results, then, raise questions about what strategies might be pursued by those who wish to improve the status of women in the profession.

The Paul Peck Scholars Program is a peer mentorship program in the first year and develops into a leadership program in subsequent years. Students in the first year of the program are paired with an upperclassman peer mentor, and have the option to continue the program through their second, third, and fourth years, during which time they participate in the leadership development aspect of the program. Through six to eight specialized courses integrated into the engineering curriculum, including a culminating service learning capstone course, students learn that the essence of mentorship, leadership and innovation lies in the ability to communicate effectively and to apply critical thinking and reasoned problem-solving skills to any situation to produce tangible and measurable results.