Differential intolerance to loss of function and missense mutations in genes that encode human matricellular proteins

Targeted gene disruption in mice has provided valuable insights into the functions of matricellular proteins. Apart from missense and loss of function mutations that have been associated with inherited diseases, however, their functions in humans remain unclear. The availability of deep exome sequencing data from over 140,000 individuals in the Genome Aggregation Database provided an opportunity to examine intolerance to loss of function and missense mutations in human matricellular genes. The probability of loss-of-function intolerance (pLI) differed widely within members of the thrombospondin, CYR61/CTGF/NOV (CCN), tenascin, small integrin-binding ligand N-linked glycoproteins (SIBLING), and secreted protein, acidic and rich in cysteine (SPARC) gene families. Notably, pLI values in humans had limited correlation with viability of the corresponding homozygous null mice. Among the thrombospondins, only THBS1 was highly loss-intolerant (pLI = 1). In contrast, Thbs1 is not essential for viability in mice. Several known thrombospondin-1 receptors were similarly loss-intolerant, although thrombospondin-1 is not the exclusive ligand for some of these receptors. The frequencies of missense mutations in THBS1 and the gene encoding its signaling receptor CD47 indicated conservation of some residues implicated in specific receptor binding. Deficits in missense mutations were also observed for other thrombospondin genes and for SPARC, SPOCK1, SPOCK2, TNR, and DSPP. The intolerance of THBS1 to loss of function in humans and elevated pLI values for THBS2, SPARC, SPOCK1, TNR, and CCN1 support important functions for these matricellular protein genes in humans, some of which may relate to functions in reproduction or responding to environmental stresses.     

Grandmaternal childcare and kinship laterality. Is rural Greece exceptional?

Grandmothers provide more childcare for their daughters' children than for those of their sons, almost everywhere. Exceptions occur where virilocal (patrilocal) postmarital residence makes the children of sons more accessible, but even under virilocality, preferential care of daughters' children, net of the effects of proximity, is often demonstrable. A unique counter-example has been reported by Pashos (2000, Evolution & Human Behavior, 21, 97–109) who found that rural Greek grandmothers cared more for their sons' children even when effects of proximity were controlled; however, this result was based on an analysis in which everything from living in the same household to living in nearby villages was treated as equally close.Here, we present new analyses that replicate Pashos's result, based on a large European survey with a finer differentiation of residential proximity. In interviews conducted in 2004–2007, rural, but not urban, Greek women indeed reported more care of sons' than of daughters' children, net of the effects of proximity and other variables, This rural reversal of the usual uterine (matrilateral) bias was not observed elsewhere in Europe. Greeks were not surveyed again until 2015, whereupon the pattern had disappeared, with rural women now exhibiting a strong uterine bias in grandchild childcare. It seems likely that the financial crisis of 2008–2009, which hit Greece especially hard, played some role in this dramatic change, but it cannot readily be traced to increases in either unemployment or multigenerational households.     

The S-Distribution A Tool for Approximation and Classification of Univariate,Unimodal Probability Distributions

In many statistical applications a data set needs to be evaluated but there is no solid information about which probability distribution might be most appropriate. Typical solutions to this problems are: to make assumptions that facilitate mathematical treatment; to use a family of distribution functions that contains all relevant distributions as special cases; or, to employ nonparametric methods. All three solutions have disadvantages since assumptions are usually difficult to justify, families of distributions contain too many parameters to be of practical use, and nonparametric methods make it difficult to characterize data in a succinct quantitative form. The S-distribution introduced here is a compromise between the conflicting goals of simplicity in analysis and generality in scope. It is characterized by four parameters, one of which reflects its location, the second one its spread, and the remaining two its shape; transformation to a standard form reduces the number of free parameters to two. Cumulatives and densities are computed numerically in fractions of seconds, key features like quantiles and moments are easily obtained, and results can be presented in terms of parameter values. The S-distribution rather accurately models different distribution functions, including central and noncentral distributions, and thus competes in flexibility with some distribution families. As an approximation, the S-distribution provides a graphical method for demonstrating relationships between distributions, such as the relationships between central F, χ² and χ^?2 or central and noncentral t, χ^-1, and normal.     

Evolutionary sequence divergence within repeated DNA families of higher plant genomes

The higher proportion of repeated DNA sequences in the garden pea (Pisum sativum) than in the mung bean (Vigna radiata), as well as other differences between these legume genomes, are consistent with a higher rate of sequence amplification in the former. This hypothesis leads to a prediction that repeated sequence families inPisum are mostly heterogeneous, as defined by Bendich and Anderson (1977), whileVigna families are homogeneous. An assay developed by these authors to distinguish between the two types of families, by comparison of reassociation rates at different temperatures, was utilized. The results forVigna defied the predictions of the assay for either homogeneous or hetereogeneous model. Evaluation of the kinetic data in light of the great diversity of repeated family copy numbers in both genomes enabled an interpretation of the results as consistent with hetereogenous families inPisum and homogeneous families inVigna. These tentative conclusions were supported by the results of a thermal denaturation (melting) assay described in the accompanying paper.Abbreviations used C_ot the product of molar concentration of DNA nucleotides and time of incubation (mol s/L) - EC_ot equivalent - C_ot the value after correction to standard reassociation conditions (120 mM sodium phosphate buffer, 60°C) - (Et)₄NCl tetraethylammonium chloride - T_m the temperature at which half of the nucleotides in solution are unpaired This paper is Carnegie Institution of Washington Department of Plant Biology Publication No. 708 and is based on a portion of a dissertation submitted by R.S.P. in partial fulfillment of the Ph.D. requirements at Stanford University     

谷子β-胡萝卜素异构酶家族基因的表达与变异分析

株型是影响谷类作物产量的重要性状, 株型改良对提高作物产量具有重要意义。独脚金内酯(strigolactones, SLs)作为一种最新被鉴定的植物激素, 其通过抑制腋芽的伸长调控分枝/分蘖的形成。β-胡萝卜素异构酶(D27s)是SLs合成途径的关键酶, 通过对谷子(Setaria italica) β-胡萝卜素异构酶典型结构域Pfam:DUF4033进行分析, 鉴定到3个谷子D27s基因家族成员(Seita.8G168400、Seita.6G088800和Seita.3G050900)。蛋白质特性分析显示, 谷子D27s蛋白由271-277个氨基酸残基组成, 分子量为30.1-30.4 kDa, 等电点为5.85-9.31, 不稳定系数介于38.48-74.47之间, 且均定位于叶绿体; 系统进化分析发现, 谷子D27s家族成员位于3个不同进化分支; 顺式作用元件预测显示, SiD27-1 (Seita.8G168400)可能参与调控生物节律、生长素介导的生长发育以及干旱和低温等胁迫应答过程。基因表达分析显示, SiD27-1在谷子多分蘖材料中表达下调, 在低磷胁迫处理下, D27s基因均能产生不同程度的响应, 并且SiD27-1的响应较其它成员更快速。单倍型分析结果表明, SiD27-1的H001单倍型为优异单倍型, 对谷子的株高、抽穗期和产量改良具有重要应用价值。综上, 推测SiD27-1极可能在SLs合成中发挥关键作用并对谷子株型产生影响。研究结果为深入揭示D27s对谷子分蘖形成的调控机制奠定了基础, 也为谷子株型分子设计育种提供了优异的等位变异位点。     

PCR‐based isolation of multigene families: lessons from the avian MHC class IIB

The amount of sequence data available today highly facilitates the access to genes from many gene families. Primers amplifying the desired genes over a range of species are readily obtained by aligning conserved gene regions, and laborious gene isolation procedures can often be replaced by quicker PCR‐based approaches. However, in the case of multigene families, PCR‐based approaches bear the often ignored risk of incomplete isolation of family members. This problem is most prominent in gene families with highly variable and thus unpredictable number of gene copies among species, such as in the major histocompatibility complex (MHC). In this study, we (i) report new primers for the isolation of the MHC class IIB (MHCIIB) gene family in birds and (ii) share our experience with isolating MHCIIB genes from an unprecedented number of avian species from all over the avian phylogeny. We report important and usually underappreciated problems encountered during PCR‐based multigene family isolation and provide a collection of measures to help significantly improving the chance of successfully isolating complete multigene families using PCR‐based approaches.     

Genome-wide association study of shank length and diameter at different developmental stages in chicken F2 resource population

In order to find SNPs and genes affecting shank traits, we performed a GWAS in a chicken F2 population of eight half-sib families from five hatches derived from reciprocal crosses between an Arian fast-growing line and an Urmia indigenous slow-growing chicken. A total of 308 birds were genotyped using a 60K chicken SNP chip. Shank traits including shank length and diameter were measured weekly from birth to 12 weeks of age. A generalized linear model and a compressed mixed linear model (CMLM) were applied to achieve the significant regions. The value of the average genomic inflation factor (λ statistic) of the CMLM model (0.99) indicated that the CMLM was more effective than the generalized linear model in controlling the population structure. The genes surrounding significant SNPs and their biological functions were identified from NCBI, Ensembl and UniProt databases. The results indicated that 12 SNPs at 12 different ages passed the LD-adjusted 5% Bonferroni significant threshold. Two SNPs were significant for shank length and nine SNPs were significant for shank diameter. The significant SNPs were located near to or inside 11 candidate genes. The results showed that a number of significant SNPs in the middle ages were higher than the rest. The MXRA8 gene was related to the significant SNP at week 1 that promotes proliferation of growth plate chondrocytes. A unique SNP of Gga_rs16689511 located on chicken Z chromosome within the LOC101747628 gene was related to shank length at three different ages of birds (weeks 8, 9 and 11). The significant SNPs for shank diameter were found at weeks 4 and 7 (four and five SNPs respectively). The identifications of SNPs and genes here could contribute to a better understanding of the genetic control of shank traits in chicken.