What are the experiences of colorectal cancer patients with biomarker testing in Canada?: a mixed methods study.

OBJECTIVE: Molecular or biomarker testing to guide targeted treatments for colorectal cancer (CRC) has advanced care, specifically by improving treatment specificity. Our objective was to explore patients' experiences and perspectives with biomarker testing in Canada. METHODS: We conducted a mixed-methods study among adults (≥ 18 years) who have been diagnosed with CRC and able to communicate in English. Quantitative data was gathered using an online survey, with questions on awareness of and experiences with biomarker testing. Qualitative data was gathered using semi-structured interviews with a sample of survey respondents to provide context to survey findings. RESULTS: Among 55 survey respondents, 76% have heard of biomarker testing and of these, 67% have had biomarker testing done. Among the 33% of respondents that have not had biomarker testing done, reasons were: not offered/referred, fear/anxiety over results, and cost. Respondents who had biomarker testing largely found biomarker testing useful (89%), though, only half indicated that they were able to understand the information on their biomarker testing report. Qualitative analysis of interview transcripts identified four themes: 1) perceived benefits of biomarker testing, 2) knowledge of biomarker testing, 3) experiences with accessing and receiving biomarker testing, and 4) recommendations for addressing challenges with biomarker testing. CONCLUSION: Altogether, our study provides insight into CRC patients' perspectives and experiences with biomarker testing. Ongoing efforts by patient organizations, providers, and policymakers to improve awareness and access to biomarker testing must be informed by the patient perspective.

Widespread Recombination Suppression Facilitates Plant Sex Chromosome Evolution.

Classical models suggest that recombination rates on sex chromosomes evolve in a stepwise manner to localize sexually antagonistic variants in the sex in which they are beneficial, thereby lowering rates of recombination between X and Y chromosomes. However, it is also possible that sex chromosome formation occurs in regions with preexisting recombination suppression. To evaluate these possibilities, we constructed linkage maps and a chromosome-scale genome assembly for the dioecious plant Rumex hastatulus. This species has a polymorphic karyotype with a young neo-sex chromosome, resulting from a Robertsonian fusion between the X chromosome and an autosome, in part of its geographic range. We identified the shared and neo-sex chromosomes using comparative genetic maps of the two cytotypes. We found that sex-linked regions of both the ancestral and the neo-sex chromosomes are embedded in large regions of low recombination. Furthermore, our comparison of the recombination landscape of the neo-sex chromosome to its autosomal homolog indicates that low recombination rates mainly preceded sex linkage. These patterns are not unique to the sex chromosomes; all chromosomes were characterized by massive regions of suppressed recombination spanning most of each chromosome. This represents an extreme case of the periphery-biased recombination seen in other systems with large chromosomes. Across all chromosomes, gene and repetitive sequence density correlated with recombination rate, with patterns of variation differing by repetitive element type. Our findings suggest that ancestrally low rates of recombination may facilitate the formation and subsequent evolution of heteromorphic sex chromosomes.

Effects of the neo-X chromosome on genomic signatures of hybridization in Rumex hastatulus.

Natural hybrid zones provide opportunities for studies of the evolution of reproductive isolation in wild populations. Although recent investigations have found that the formation of neo-sex chromosomes is associated with reproductive isolation, the mechanisms remain unclear in most cases. Here, we assess the contemporary structure of gene flow in the contact zone between largely allopatric cytotypes of the dioecious plant Rumex hastatulus, a species with evidence of sex chromosome turn-over. Males to the west of the Mississippi river, USA, have an X and a single Y chromosome, whereas populations to the east of the river have undergone a chromosomal rearrangement giving rise to a larger X and two Y chromosomes. Using reduced-representation sequencing, we provide evidence that hybrids form readily and survive multiple backcross generations in the field, demonstrating the potential for ongoing gene flow between the cytotypes. Cline analysis of each chromosome separately captured no signals of difference in cline shape between chromosomes. However, principal component regression revealed a significant increase in the contribution of individual SNPs to inter-cytotype differentiation on the neo-X chromosome, but no correlation with recombination rate. Cline analysis revealed that the only SNPs with significantly steeper clines than the genome average were located on the neo-X. Our data are consistent with a role for neo-sex chromosomes in reproductive isolation between R. hastatulus cytotypes. Our investigation highlights the importance of studying plant hybrid zones for understanding the evolution of sex chromosomes.

Allele frequency dynamics under sex-biased demography and sex-specific inheritance in a pedigreed jay population.

Sex-biased demography, including sex-biased survival or migration, can alter allele frequency changes across the genome. In particular, we can expect different patterns of genetic variation on autosomes and sex chromosomes due to sex-specific differences in life histories, as well as differences in effective population size, transmission modes, and the strength and mode of selection. Here, we demonstrate the role that sex differences in life history played in shaping short-term evolutionary dynamics across the genome. We used a 25-year pedigree and genomic dataset from a long-studied population of Florida Scrub-Jays (Aphelocoma coerulescens) to directly characterize the relative roles of sex-biased demography and inheritance in shaping genome-wide allele frequency trajectories. We used gene dropping simulations to estimate individual genetic contributions to future generations and to model drift and immigration on the known pedigree. We quantified differential expected genetic contributions of males and females over time, showing the impact of sex-biased dispersal in a monogamous system. Due to female-biased dispersal, more autosomal variation is introduced by female immigrants. However, due to male-biased transmission, more Z variation is introduced by male immigrants. Finally, we partitioned the proportion of variance in allele frequency change through time due to male and female contributions. Overall, most allele frequency change is due to variance in survival and births. Males and females make similar contributions to autosomal allele frequency change, but males make higher contributions to allele frequency change on the Z chromosome. Our work shows the importance of understanding sex-specific demographic processes in characterizing genome-wide allele frequency change in wild populations.

Chromosome Evolution: Infectious Sex Chromosomes in the African Monarch Butterfly.

Why do some organisms have multiple sex chromosomes? New findings in an African butterfly suggest a prominent role for a bacterial parasite.

Ancestral and neo-sex chromosomes contribute to population divergence in a dioecious plant.

Empirical evidence from several animal groups suggests sex chromosomes disproportionately contribute to reproductive isolation. This effect may be enhanced when sex chromosomes are associated with turnover of sex determination systems resulting from structural rearrangements to the chromosomes. We investigated these predictions in the dioecious plant Rumex hastatulus, which is composed of populations of two different sex chromosome cytotypes caused by an X-autosome fusion. Using population genomic analyses, we investigated the demographic history of R. hastatulus and explored the contributions of ancestral and neo-sex chromosomes to population genetic divergence. Our study revealed that the cytotypes represent genetically divergent populations with evidence for historical but not contemporary gene flow between them. In agreement with classical predictions, we found that the ancestral X chromosome was disproportionately divergent compared with the rest of the genome. Excess differentiation was also observed on the Y chromosome, even when we used measures of differentiation that control for differences in effective population size. Our estimates of the timing of the origin of neo-sex chromosomes in R. hastatulus are coincident with cessation of gene flow, suggesting that the chromosomal fusion event that gave rise to the origin of the XYY cytotype may have also contributed to reproductive isolation.

Evolutionary Genomics of Plant Gametophytic Selection.

It has long been recognized that natural selection during the haploid gametophytic phase of the plant life cycle may have widespread importance for rates of evolution and the maintenance of genetic variation. Recent theoretical advances have further highlighted the significance of gametophytic selection for diverse evolutionary processes. Genomic approaches offer exciting opportunities to address key questions about the extent and effects of gametophytic selection on plant evolution and adaptation. Here, we review the progress and prospects for integrating functional and evolutionary genomics to test theoretical predictions, and to examine the importance of gametophytic selection on genetic diversity and rates of evolution. There is growing evidence that selection during the gametophyte phase of the plant life cycle has important effects on both gene and genome evolution and is likely to have important pleiotropic effects on the sporophyte. We discuss the opportunities to integrate comparative population genomics, genome-wide association studies, and experimental approaches to further distinguish how differential selection in the two phases of the plant life cycle contributes to genetic diversity and adaptive evolution.

The effects of haploid selection on Y chromosome evolution in two closely related dioecious plants.

The evolution of sex chromosomes is usually considered to be driven by sexually antagonistic selection in the diploid phase. However, selection during the haploid gametic phase of the lifecycle has recently received theoretical attention as possibly playing a central role in sex chromosome evolution, especially in plants where gene expression in the haploid phase is extensive. In particular, male-specific haploid selection might favor the linkage of pollen beneficial alleles to male sex determining regions on incipient Y chromosomes. This linkage might then allow such alleles to further specialize for the haploid phase. Purifying haploid selection is also expected to slow the degeneration of Y-linked genes expressed in the haploid phase. Here, we examine the evolution of gene expression in flower buds and pollen of two species of Rumex to test for signatures of haploid selection acting during plant sex chromosome evolution. We find that genes with high ancestral pollen expression bias occur more often on sex chromosomes than autosomes and that genes on the Y chromosome are more likely to become enriched for pollen expression bias. We also find that genes with low expression in pollen are more likely to be lost from the Y chromosome. Our results suggest that sex-specific haploid selection during the gametophytic stage of the lifecycle may be a major contributor to several features of plant sex chromosome evolution.

Genomic Loss and Silencing on the Y Chromosomes of Rumex.

Across many unrelated lineages of plants and animals, Y chromosomes show a recurrent pattern of gene degeneration and loss, but the relative importance of inefficient selection, adaptive gene silencing, and neutral genetic drift in causing degeneration remain poorly understood. Here, we use next-generation genome and transcriptome sequencing to investigate patterns of ongoing Y chromosome degeneration in two annual plant species of Rumex (Polygonaceae) differing in their degree of degeneration and sex chromosome heteromorphism. We find evidence for both gene loss as well as silencing in these young plant sex chromosomes. Our analyses revealed significantly more gene deletion relative to silencing in R. rothschildianus, which has had a larger nonrecombining region for a longer period than R. hastatulus, consistent with this system being at a more advanced stage of degeneration. Intra- and interspecific comparisons of genomic coverage and heterozygosity indicated that loss of expression precedes gene deletion, implying that the final stages of mutation accumulation and gene loss may often occur neutrally. We found no evidence for adaptive silencing of genes that have lost expression. Our results suggest that the initial spread of deleterious regulatory variants and/or epigenetic silencing may be an important driver of early degeneration of Y chromosomes.

The spotted gar genome illuminates vertebrate evolution and facilitates human-teleost comparisons.

To connect human biology to fish biomedical models, we sequenced the genome of spotted gar (Lepisosteus oculatus), whose lineage diverged from teleosts before teleost genome duplication (TGD). The slowly evolving gar genome has conserved in content and size many entire chromosomes from bony vertebrate ancestors. Gar bridges teleosts to tetrapods by illuminating the evolution of immunity, mineralization and development (mediated, for example, by Hox, ParaHox and microRNA genes). Numerous conserved noncoding elements (CNEs; often cis regulatory) undetectable in direct human-teleost comparisons become apparent using gar: functional studies uncovered conserved roles for such cryptic CNEs, facilitating annotation of sequences identified in human genome-wide association studies. Transcriptomic analyses showed that the sums of expression domains and expression levels for duplicated teleost genes often approximate the patterns and levels of expression for gar genes, consistent with subfunctionalization. The gar genome provides a resource for understanding evolution after genome duplication, the origin of vertebrate genomes and the function of human regulatory sequences.