Pavel M. Borodin

Predicting human height by Victorian and genomic methods

In the Victorian era, Sir Francis Galton showed that ‘when dealing with the transmission of stature from parents to children, the average height of the two parents, … is all we need care to know about them’ (1886). One hundred and twenty-two years after Galtons work was published, 54 loci showing strong statistical evidence for association to human height were described, providing us with potential genomic means of human height prediction. In a population-based study of 5748 people, we find that a 54-loci genomic profile explained 4–6% of the sex- and age-adjusted height variance, and had limited ability to discriminate tall/short people, as characterized by the area under the receiver-operating characteristic curve (AUC). In a family-based study of 550 people, with both parents having height measurements, we find that the Galtonian mid-parental prediction method explained 40% of the sex- and age-adjusted height variance, and showed high discriminative accuracy. We have also explored how much variance a genomic profile should explain to reach certain AUC values. For highly heritable traits such as height, we conclude that in applications in which parental phenotypic information is available (eg, medicine), the Victorian Galtons method will long stay unsurpassed, in terms of both discriminative accuracy and costs. For less heritable traits, and in situations in which parental information is not available (eg, forensics), genomic methods may provide an alternative, given that the variants determining an essential proportion of the traits variation can be identified.

Segregation analysis of idiopathic scoliosis: demonstration of a major gene effect.

Segregation analysis using a model with age and gender effects was applied to 101 pedigrees ascertained through a proband with idiopathic scoliosis. The transmission probability model was used to detect major gene effect. When we analyzed the pedigrees where affected status was assigned to persons with a Cobbs angle of more than 5 degrees we did not detect a significant major gene effect. However, when the affected status was assigned to persons with pronounced forms of disease only (a curve of at least 11 degrees) a significant contribution of a major causal gene could be established and inheritance could be described according to a dominant major gene diallele model, assuming incomplete sex and age dependent penetrance of genotypes. According to this model, the pronounced forms of idiopathic scoliosis should never occur in the absence of the mutant allele. This indicates that only the carriers of the mutant allele develop pronounced forms of the disease. At the same time, only a fraction of the carriers of the mutant gene should manifest the disease (30% of males and 50% of females).

Chromosomal rearrangements do not seem to affect the gene flow in hybrid zones between karyotypic races of the common shrew (Sorex araneus).

Chromosomal rearrangements are proposed to promote genetic differentiation between chromosomally differentiated taxa and therefore promote speciation. Due to their remarkable karyotypic polymorphism, the shrews of the Sorex araneus group were used to investigate the impact of chromosomal rearrangements on gene flow. Five intraspecific chromosomal hybrid zones characterized by different levels of karyotypic complexity were studied using 16 microsatellites markers. We observed low levels of genetic differentiation even in the hybrid zones with the highest karyotypic complexity. No evidence of restricted gene flow between differently rearranged chromosomes was observed. Contrary to what was observed at the interspecific level, the effect of chromosomal rearrangements on gene flow was undetectable within the S. araneus species.

Chromosomal evolution of the Common Shrew Sorex araneus L.from the Southern Ural and Siberia in the postglacial period

This paper summarizes a series of studies on chromosomal geography of the common shrew Sorex araneusL. in Siberia and the Southern Urals. Chromosomal races inhabiting the Southern Urals and the Western Siberian Plain sequentially replace each other in the latitudinal direction. In this region, karyotypes of each two adjacent races differ from each other by a single whole-arm reciprocal translocation. In the Eastern Siberian and Altai branches, the neighboring races differ mainly in the number or set of metacentric chromosomes. Analysis of the race distribution in the common shrew in the context of paleoecology of the glacial and postglacial period allowed us to reconstruct the sequence of events leading to the establishment of the present-day structure of the species S. araneus.

The X-autosome translocation in the common shrew (Sorex araneus L.): late replication in female somatic cells and pairing in male meiosis

Common shrews have an XX/XY1Y2 sex chromosome system, with the “X” chromosome being a translocation (tandem fusion) between the “original” X and an autosome; in males this autosome is represented by the Y2 chromosome. From G-banded chromosomes, the Y2 is homologous to the long arm and centromeric part of the short arm of the X. The region of the X that is homologous to the Y2 and also the telomeric region of the short arm of the X were found to be early replicating in somatic cells from a female shrew after 5-bromo-2′-deoxyuridine (BrdU) treatment in vitro. The remainder of the short arm of the X was shown to be late replicating. Electron microscopic examination of synaptonemal complexes in males at pachytene revealed pairing of the Y2 axis with the long arm of the X, and Y1 with the short arm. At early stages of pachytene, there is apparently extensive nonhomologous pairing between the X and Y1. In essence, the short arm of the shrew X chromosome behaves like a typical eutherian X chromosome (it is inactivated in female somatic cells and is paried with the Y1 during male meiosis) while the long arm behaves like an autosome (escapes the inactivation and pairs with the Y2).

Morphometric difference between the Novosibirsk and Tomsk chromosome races of Sorex araneus in a zone of parapatry.

A hybrid zone between the Novosibirsk and Tomsk chromosome races of the common shrewSorex araneus Linnaeus, 1758 was found near Novosibirsk city (West Siberia, Russia) in an area unimpeded by geographic barriers. In this zone, the shrews of both races and their hybrids were trapped and karyotyped and 22 features of their cranial and postcranial skeleton were measured. Canonical discriminant analysis revealed 3 distinct groups of individuals, which corresponded to the 3 karyotypic categories involved in the analysis. The first discriminant function reflected the differences in the size of skeletal elements. The Novosibirsk shrews and the hybrids were significantly smaller than the Tomsk shrews. The second discriminant function was interpreted as a parameter of skeletal proportionality. The hybrids were significantly less proportional than the parental races. This study revealed one of the clearest examples of morphological differentiation between chromosome races of the common shrew.

Linkage and association analyses of glaucoma related traits in a large pedigree from a Dutch genetically isolated population

Background Despite extensive research on the genetic determinants of glaucoma, the genes identified to date explain only a small proportion of cases in the general population. Methods Genome-wide linkage and association analyses of quantitative traits related to glaucoma were performed: intraocular pressure, size and morphology of the optic disc (individual and combined by method of principal components) and thickness of the retinal nerve fibre layer (RNFL), in a large pedigree from a genetically isolated Dutch population. Results For the size of the optic disc, the study demonstrated a significant linkage signal (logarithm of odds (LOD)=3.6) at the LRP1B region on chromosome 2q21.2-q22.2 and significant association (p=8.95×10−12) with the previously reported CDC7/TGFBR3 locus at 1p22. For parameters describing morphology of the optic disc, the study obtained significant linkage signal (LOD=4.6) at regions SIRPA and RNF24/PANK2 at 20p13 (false discovery rate (FDR) based q value <0.05) and genome-wide significant association (p=2.38×10−9) with a common variant in the RERE gene at 1p36. Suggestive linkage and association signals indicated loci for morphology of the optic disc at 2q31-q33 (IGFBP2 locus) and for RNFL thickness at 3p22.2 (DCLK3 locus) and 14q22-q23 (SIX1 locus). Conclusion This study identified new linkage regions at 20p13 (SIRPA and RNF24/PANK2 loci) and 2q33-q34 (IGFBP2 locus) for parameters describing morphology of the optic disc. The results of the study also suggested common genetic control of these parameters and RNFL thickness by SIX1 and doublecotin family genes. Finally, association signals for the recently reported RERE and LRP1B loci and the well known CDC7, TGFBR3, and ATOH7 loci were replicated.

Multiple independent evolutionary losses of XY pairing at meiosis in the grey voles

In many eutherian mammals, X–Y chromosome pairing and recombination is required for meiotic progression and correct sex chromosome disjunction. Arvicoline rodents present a notable exception to this meiotic rule, with multiple species possessing asynaptic sex chromosomes. Most asynaptic vole species belong to the genus Microtus sensu lato. However, many of the species both inside and outside the genus Microtus display normal X–Y synapsis at meiosis. These observations suggest that the synaptic condition was present in the common ancestor of all voles, but gaps in current taxonomic sampling across the arvicoline phylogeny prevent identification of the lineage(s) along which the asynaptic state arose. In this study, we use electron and immunofluorescent microscopy to assess heterogametic sex chromosome pairing in 12 additional arvicoline species. Our sample includes ten species of the tribe Microtini and two species of the tribe Lagurini. This increased breadth of sampling allowed us to identify asynaptic species in each major Microtine lineage. Evidently, the ability of the sex chromosomes to pair and recombine in male meiosis has been independently lost at least three times during the evolution of Microtine rodents. These results suggest a lack of evolutionary constraint on X–Y synapsis in Microtini, hinting at the presence of alternative molecular mechanisms for sex chromosome segregation in this large mammalian tribe.

Novosibirsk revisited 24 years on: chromosome polymorphism in the Novosibirsk population of the common shrew Sorex araneus L.

A Robertsonian fusion polymorphism in the common shrew (Sorex araneus L.), first described in Academgorodok near Novosibirsk (western Siberia) in 1970–72, was re-examined in 1994–95. The polymorphism in the 1970s involved chromosome arm combinations go, jl, mp and qr, i.e. each of these combinations was present in both a metacentric and a twin-acrocentric state in the population at that time. The twin-acrocentric morph for go occurred at low frequency in 1970–72 and was not observed in 1994–95. The polymorphism for arm combinations jl, mp and qr was still observed in 1994–95 and there was no significant difference in metacentric/twin-acrocentric frequencies compared with the previous sample. This is the third well-documented example in which the chromosome polymorphism in the common shrew has been found to be unchanged over a period of 20+ years. Although the polymorphism for qr may be associated with a chromosomal hybrid zone with a cline centre 200 km away, there is no definitive explanation for the other polymorphisms.

Pattern of X-Y chromosome pairing in the Taiwan vole, Microtus kikuchii.

Pairing of X and Y chromosomes at meiotic prophase and the G- and C-banding patterns and nucleolar organizer region (NOR) distribution were analyzed in Microtus kikuchii. M. kikuchii is closely related to M. oeconomus and M. montebelli, karyologically and systematically. The formation of a synaptonemal complex between the X and Y chromosomes at pachytene and end-to-end association at diakinesis--metaphase I are only observed in three species in the genus Microtus; M. kikuchii, M. oeconomus, and M. montebelli. All the other species that have been studied so far have had asynaptic X-Y chromosomes. These data confirm that M. kikuchii, M. oeconomus, and M. montebelli are very closely related, and support the separation of asynaptic and synaptic groups on the phylogenetic tree.