High mutation rates have driven extensive structural polymorphism among human Y chromosomes

Although much structural polymorphism in the human genome has been catalogued, the kinetics of underlying change remain largely unexplored. Because human Y chromosomes are clonally inherited, it has been possible to capture their detailed relationships in a robust, worldwide genealogical tree. Examination of structural variation across this tree opens avenues for investigating rates of underlying mutations. We selected one Y chromosome from each of 47 branches of this tree and searched for large-scale variation. Four chromosomal regions showed extensive variation resulting from numerous large-scale mutations. Within the tree encompassed by the studied chromosomes, the distal-Yq heterochromatin changed length > or = 12 times, the TSPY gene array changed length > or = 23 times, the 3.6-Mb IR3/IR3 region changed orientation > or = 12 times and the AZFc region was rearranged > or = 20 times. After determining the total time spanned by all branches of this tree (approximately 1.3 million years or 52,000 generations), we converted these mutation counts to lower bounds on rates: > or = 2.3 x 10(-4), > or = 4.4 x 10(-4), > or = 2.3 x 10(-4) and > or = 3.8 x 10(-4) large-scale mutations per father-to-son Y transmission, respectively. Thus, high mutation rates have driven extensive structural polymorphism among human Y chromosomes. At the same time, we found limited variation in the copy number of Y-linked genes, which raises the possibility of selective constraints.     

Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus

Idiopathic congenital nystagmus is characterized by involuntary, periodic, predominantly horizontal oscillations of both eyes. We identified 22 mutations in FRMD7 in 26 families with X-linked idiopathic congenital nystagmus. Screening of 42 singleton cases of idiopathic congenital nystagmus (28 male, 14 females) yielded three mutations (7%). We found restricted expression of FRMD7 in human embryonic brain and developing neural retina, suggesting a specific role in the control of eye movement and gaze stability.     

A population-specific HTR2B stop codon predisposes to severe impulsivity

Impulsivity, describing action without foresight, is an important feature of several psychiatric diseases, suicidality and violent behaviour. The complex origins of impulsivity hinder identification of the genes influencing it and the diseases with which it is associated. Here we perform exon-focused sequencing of impulsive individuals in a founder population, targeting fourteen genes belonging to the serotonin and dopamine domain. A stop codon in HTR2B was identified that is common (minor allele frequency >?1%) but exclusive to Finnish people. Expression of the gene in the human brain was assessed, as well as the molecular functionality of the stop codon, which was associated with psychiatric diseases marked by impulsivity in both population and family-based analyses. Knockout of Htr2b increased impulsive behaviours in mice, indicative of predictive validity. Our study shows the potential for identifying and tracing effects of rare alleles in complex behavioural phenotypes using founder populations, and indicates a role for HTR2B in impulsivity.     

Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma

Through exomic sequencing of ten hepatitis C virus (HCV)-associated hepatocellular carcinomas (HCC) and subsequent evaluation of additional affected individuals, we discovered novel inactivating mutations of ARID2 in four major subtypes of HCC (HCV-associated HCC, hepatitis B virus (HBV)-associated HCC, alcohol-associated HCC and HCC with no known etiology). Notably, 18.2% of individuals with HCV-associated HCC in the United States and Europe harbored ARID2 inactivation mutations, suggesting that ARID2 is a tumor suppressor gene that is relatively commonly mutated in this tumor subtype.     

Seed bank dynamics and habitat indicators of Arctomecon californica, a rare plant in a fragmented desert environment

Protection of endangered desert plant species is frequently complicated by a lack of information about seeds, the most stress-resistant and populous life stage. We studied the relative locations of seeds and plants of a rare endangered herbaceous perennial, the Las Vegas bearpoppy ( Arctomecon californica ) in seven 1-ha sites randomly located within a 100-ha study area that was slated for development in Las Vegas, Nevada. We also measured the physical and biological attributes of the environment supporting the seeds and plants, including soil hardness, rock cover, cryptogamic crust cover, and associated vegetation. Arctomecon californica seed density was 0.651 seeds · m –2 , and seeds were found throughout the top 4 cm of soil. Seed viability among sites ranged from 26% to 79%; however, no significant changes between depths were detected. The spatial distribution of the seed bank coincided with the current A. californica adult distribution only in sites with both a high plant density and high numbers of seeds. Arctomecon californica adults occupied open areas within the gypsum environment that supported significantly less vegetative cover than the surrounding area. We observed a positive association between A. californica adults and shadscale ( Atriplex confertifolia ) and a negative association with 7 other plant species among sites. Sites with an indurated abiotic crust hosted higher numbers of A. californica adults than sites with softer soils. However, rock cover, cryptogamic crust cover, and soil hardness were poor explanatory factors for characterizing A. californica presence. We suggest that land managers should incorporate seed bank census into monitoring programs due to the extreme year-to-year fluctuations in A. californica plant population densities. A menudo la protección de especies de plantas desérticas en peligro de extinción se ve complicada por la falta de información sobre las semillas, la etapa de vida más abundante y resistente al estrés. Estudiamos la ubicación relativa de semillas y plantas de “Las Vegas bearpoppy” ( Arctomecon californica ), una planta perenne en peligro de extinción, en 7 sitios de 1 ha. localizados al azar dentro de un área de estudio de 100 ha que estaba destinada a la urbanización en Las Vegas, Nevada (E.U.A.). También medimos los atributos físicos y biológicos del ambiente que sostiene las semillas y plantas, tales como dureza del suelo, rocosidad, cobertura de costra cryptógama y vegetación asociada. La densidad de semillas de A. californica fue 0.651 semillas · m –2 y se observó en los 4 cm superiores del suelo. La viabilidad de las semillas varió del 26% al 79% entre los sitios; sin embargo, no detectamos cambios significativos entre profundidades. La distribución espacial del banco de semillas coincidió con la distribución actual de adultos de A. californica, sólo en sitios que tuvieron una alta densidad de plantas y altos números de semillas. Los adultos de A. californica ocuparon áreas abiertas dentro del ambiente de yeso que sostenía significativamente menos cobertura vegetal que las áreas circunvecinas. Observamos una asociación positiva entre los adultos de A. californica y el chamizo ( Atriplex confertifolia ) y una asociación negativa con siete otras especies de plantas entre sitios. Los sitios con una costra abiótica endurecida albergaron más adultos de A. californica que los sitios con suelos más blandos. No obstante, la cubierta rocosa, la costra cryptógama y la dureza del suelo fueron inadecuadas como factores para caracterizar la presencia de A. californica. Sugerimos que los manejadores de tierras deben incorporar censos de bancos de semillas en los programas de monitoreo, debido a las fluctuaciones extremas de un año a otro en la densidad poblacional de A. californica. Normal 0 MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:"Times New Roman";}     

Rheumatoid arthritis susceptibility loci at chromosomes 10p15, 12q13 and 22q13

The WTCCC study identified 49 SNPs putatively associated with rheumatoid arthritis at P = 1 x 10(-4) - 1 x 10(-5) (tier 3). Here we show that three of these SNPs, mapping to chromosome 10p15 (rs4750316), 12q13 (rs1678542) and 22q13 (rs3218253), are also associated (trend P = 4 x 10(-5), P = 4 x 10(-4) and P = 4 x 10(-4), respectively) in a validation study of 4,106 individuals with rheumatoid arthritis and an expanded reference group of 11,238 subjects, confirming them as true susceptibility loci in individuals of European ancestry.     

Further morphological and molecular studies of driftwood hoppers (Crustacea: Amphipoda: Talitridae) from Mediterranean/north-east Atlantic coastlines

An unknown talitrid was discovered in 2011 in the Swale, UK, living in driftwood. Sequencing of multiple mitochondrial and nuclear genes (cytochrome oxidase I, 18S rDNA and 28S rDNA) confirms that the unknown taxon was close to Orchestia mediterranea A. Costa 1857. The driftwood in which it was found was of Douglas fir (Pseudotsuga menziesii), probably imported from North America. Relative growth methods allow us to reject the null hypothesis that the unknown taxon was a juvenile Orchestia mediterranea. This is because the unknown taxon initiates sexual maturation at an earlier moult number (neoteny) and is predicted to reach terminal moult stages at a much smaller size (dwarfism) than its closest relative O. mediterranea. Both molecular and morphological data confirm that the unknown taxon from the Swale, UK, is a new driftwood specialist taxon, distantly related to the driftwood specialist genus Macarorchestia. Additional data for body length and sex ratios are presented for Macarorchestia. In addition, relative growth methods have shown that the driftwood species Orchestia microphtalma Amanieu and Salvat 1964 is closer to the genus Macarorchestia rather than to the wrack generalist one, Orchestia. This evidence is in line with the molecular results that do not cluster morphologically defined species of Orchestia monophyletically.