Inference of selection gradients using performance measures as fitness proxies

O.D.F. is supported by the Natural Sciences and Engineering Research Council of Canada and the Madame Vigdís Finnbogadóttir Scholarship. M.B.M. is supported by a University Research Fellowship from the Royal Society (London).1.  Selection coefficients, i.e., selection differentials and gradients, are useful for quantifying selection and for making comparisons across traits and organisms, because they appear in known equations for relating selection and genetic variation to one another and to evolutionary change. However, selection coefficients can only be estimated in organisms where traits and fitness (components) can be measured. This is probably a major contributor to taxonomic biases of selection studies. Aspects of organismal performance, i.e., quantities that are likely to be positively related to fitness components, such as body size, are sometimes used as proxies for fitness, i.e., used in place of fitness components in regression-based selection analysis. To date, little theory exists to inform empirical studies about whether such procedures may yield selection coefficients with known relationships to genetic variation and evolution. 2.  We show that the conditions under which performance measures can be used as proxies for fitness are very limited. Such analyses require that the regression of fitness on the proxy is linear and goes through the origin. We illustrate how fitness proxies may be used in conjunction with information about the performance-fitness relationship, and clarify how this is different from substituting fitness proxies for fitness components in selection analyses. 3.  We apply proxy-based and fitness component-based selection analysis to a system where traits, a performance measure (size; similar to proxies that are commonly used in place of fitness), and a more proximate fitness measure, are all available on the same set of individuals. We find that proxy-based selection gradients are poorly reflective of selection gradients estimated using fitness components, even when proxy-fitness relationships are quite strong and reasonably linear. 4.  We discuss the implications for proxy-based selection analysis. We emphasise that measures of organismal performance, such as size, may in many cases provide useful information that can contribute to quantitative inferences about natural selection, and their use could allow quantitative inference about selection to be conducted in a wider range of taxa. However, such inferences require quantitative analysis of both trait-performance and performance-fitness relationships, rather than substitution of performance for measures of fitness or fitness components.PostprintPeer reviewe

Coming to terms with heritability

The complex mechanisms of heredity are little appreciated by non-specialists, in some measure, because of misunderstandings that are perpetuated when words used for technical terms have other, more widely understood, folk meanings. When a word has both technical and folk meanings, it is the responsibility of the specialist to avoid promoting confusion by either using extremely cautious and precise language when using the term or, in cases when confusion is inevitable, abandoning the term in favor of one without a widely understood folk meaning. The study of heredity is beset by such confusion, and the term heritability appears to be at the heart of some of the confusion. In this article, I discuss both the technical and folk meanings of heritability and examine the bridge between them. By continuing to use the term heritability, we risk promulgating serious misunderstanding about the workings of heredity, therefore I suggest selectability as an alternative term to avoid such pitfalls.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42804/1/10709_2005_Article_BF02259512.pd

PHIP - a novel candidate breast cancer susceptibility locus on 6q14.1

Most non-BRCA1/2 breast cancer families have no identified genetic cause. We used linkage and haplotype analyses in familial and sporadic breast cancer cases to identify a susceptibility locus on chromosome 6q. Two independent genome-wide linkage analysis studies suggested a 3 Mb locus on chromosome 6q and two unrelated Swedish families with a LOD > 2 together seemed to share a haplotype in 6q14.1. We hypothesized that this region harbored a rare high-risk founder allele contributing to breast cancer in these two families. Sequencing of DNA and RNA from the two families did not detect any pathogenic mutations. Finally, 29 SNPs in the region were analyzed in 44,214 cases and 43,532 controls from BCAC, and the original haplotypes in the two families were suggested as low-risk alleles for European and Swedish women specifically. There was also some support for one additional independent moderate-risk allele in Swedish familial samples. The results were consistent with our previous findings in familial breast cancer and supported a breast cancer susceptibility locus at 6q14.1 around the PHIP gene.Peer reviewe

Polymorphisms in genes of melatonin biosynthesis and signaling support the light-at-night hypothesis for breast cancer

Light-at-night triggers the decline of pineal gland melatonin biosynthesis and secretion and is an IARC-classified probable breast-cancer risk factor. We applied a large-scale molecular epidemiology approach to shed light on the putative role of melatonin in breast cancer. We investigated associations between breast-cancer risk and polymorphisms at genes of melatonin biosynthesis/signaling using a study population of 44,405 women from the Breast Cancer Association Consortium (22,992 cases, 21,413 population-based controls). Genotype data of 97 candidate single nucleotide polymorphisms (SNPs) at 18 defined gene regions were investigated for breast-cancer risk effects. We calculated adjusted odds ratios (ORs) and 95% confidence intervals (CI) by logistic regression for the main-effect analysis as well as stratified analyses by estrogen- and progesterone-receptor (ER, PR) status. SNP-SNP interactions were analyzed via a two-step procedure based on logic regression. The Bayesian false-discovery probability (BFDP) was used for all analyses to account for multiple testing. Noteworthy associations (BFDP < 0.8) included 10 linked SNPs in tryptophan hydroxylase 2 (TPH2) (e.g. rs1386492: OR = 1.07, 95% CI 1.02–1.12), and a SNP in the mitogen-activated protein kinase 8 (MAPK8) (rs10857561: OR = 1.11, 95% CI 1.04–1.18). The SNP-SNP interaction analysis revealed noteworthy interaction terms with TPH2- and MAPK-related SNPs (e.g. rs1386483R ∧ rs1473473D ∧ rs3729931D: OR = 1.20, 95% CI 1.09–1.32). In line with the light-at-night hypothesis that links shift work with elevated breast-cancer risks our results point to SNPs in TPH2 and MAPK-genes that may impact the intricate network of circadian regulation

Breast cancer risk factors and survival by tumor subtype: pooled analyses from the breast cancer association consortium

Background: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype.Methods: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer-specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype.Results: There was no evidence of heterogeneous associations between risk factors and mortality by subtype (P-adj > 0.30). The strongest associations were between all-cause mortality and BMI >= 30 versus 18.5-25 kg/m(2) [HR (95% confidence interval (CI), 1.19 (1.06-1.34)]; current versus never smoking [1.37 (1.27-1.47)], high versus low physical activity [0.43 (0.21-0.86)], age >= 30 years versus 0-= 10 years since last full-term birth [1.31 (1.11-1.55)]; ever versus never use of oral contraceptives [0.91 (0.87-0.96)]; ever versus never use of menopausal hormone therapy, including current estrogen-progestin therapy [0.61 (0.54-0.69)]. Similar associations with breast cancer mortality were weaker; for example, 1.11 (1.02-1.21) for current versus never smoking.Conclusions: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype.Impact: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.Surgical oncolog

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers