Search

The inactivation of ancestral protein‐coding genes (gene loss) can be associated with phenotypic modifications. Within placental mammals, repeated losses of PNLIPRP1 (gene inhibiting fat digestion) occurred preferentially in strictly herbivorous species, whereas repeated NR1I3 losses (gene involved in detoxification) occurred preferentially in strictly carnivorous species. It was hypothesized that lower fat contents of herbivorous diets and lower toxin contents of carnivorous diets cause relaxed selection pressure on these genes, resulting in the accumulation of mutations and ultimately to convergent gene losses. However, because herbivorous and carnivorous diets differ vastly in their composition, a fine‐grained analysis is required for hypothesis testing. We generated a trait matrix recording diet and semi‐quantitative estimates of fat and toxin consumption for 52 placental species. By including data from 31 fossil taxa, we reconstructed the ancestral diets in major lineages (grundplan reconstruction). We found support that PNLIPRP1 loss is primarily associated with low levels of fat intake and not simply with herbivory/carnivory. In particular, PNLIPRP1 loss also occurred in carnivorous lineages feeding on a fat‐poor diet, suggesting that the loss of this gene may be beneficial for occupying ecological niches characterized by fat‐poor food resources. Similarly, we demonstrated that carnivorous species are indeed less exposed to diet‐related toxins, suggesting that the loss of NR1I3 and related genes (NR1I2 and UGT1A6) resulted from relaxed selection pressure. This study illustrates the need of detailed phenotype studies to obtain a deeper understanding of factors underlying gene losses and to progress in understanding genomic causes of phenotypic variation in mammals. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Are the genes that gained novel expression in the endometria of Eutherian (placental) mammals more likely to be dysregulated in patients with endometrial-associated recurrent early pregnancy loss (REPL)? SUMMARY ANSWER There was a significant enrichment of genes dysregulated in REPL patients among the Eutherian-specific endometrial genes. WHAT IS KNOWN ALREADY Pregnancy loss is the most common complication of human pregnancy. REPL has multiple etiologies, including dysregulation of endometrial function, leading to ‘suboptimal’ implantation. Although the implantation process is tightly regulated in Eutherian (placental) mammals, the molecular factors contributing to dysregulated endometrial gene expression patterns in women with REPL are largely unknown. STUDY DESIGN, SIZE, DURATION Endometrial biopsies were obtained from 32 REPL patients during the mid-luteal phase, and evaluated for glandular development arrest based on elevated nuclear cyclin E levels in gland cells, and for out-of-phase endometrial development based on histology. Gene expression levels were measured using Illumina Human HT-12v4 BeadChip arrays. PARTICIPANTS/MATERIALS, SETTING, METHODS Differentially expressed genes were identified between patients with (i) out-of-phase (n = 10) versus normal (n = 22) histological dating and (ii) abnormally elevated (n = 9) versus normal (n = 23) cyclin E levels in the nuclei of endometrial glands, using a likelihood ratio test. Enrichment of dysregulated genes in REPL endometria among Eutherian-specific genes was tested by permutation. Gene ontology and pathway enrichment analyses were carried out for the dysregulated genes. MAIN RESULTS AND THE ROLE OF CHANCE Fifty-eight and eighty-one genes were identified as differentially expressed at P < 0.001 in women with out-of-phase histological dating and abnormally elevated glandular cyclin E levels, respectively. Genes that were recruited into endometrial expression during the evolution of pregnancy in Eutherian mammals were significantly enriched for dysregulated genes (P = 0.002 for histology, P = 0.021 for cyclin E), as well as for genes involved in immune response and signaling pathways with essential roles in implantation and endometrial biology. LIMITATIONS, REASONS FOR CAUTION Small sample size limits the statistical power to detect dysregulated genes, and the lack of non-REPL control women does not allow us to test for the contribution of these genes to overall risk of REPL. WIDER IMPLICATIONS OF THE FINDINGS Enrichment of functional gene categories, as well as genes gained expression in the Eutherian endometria, help to identify molecular etiologies that contribute to normal functioning of the endometrium. These pathways are also strong candidates for successful pregnancy outcomes. Using the evolutionary history of mammalian gene expression in the endometrial tissue may be a promising approach to discover genes involved in female reproductive disorders. STUDY FUNDING/COMPETING INTEREST(S) This work is supported by National Institutes of Health (NIH) grant R01 HD21244 to C.O. Authors declare no competing interests. [ABSTRACT FROM PUBLISHER]

Abstract: Background: Natural variation offers a powerful approach for assigning function to DNA sequence—a pressing challenge in the age of high throughput sequencing technologies. Scope of Review: Here we review comparative genomic approaches that are bridging the sequence–function and genotype–phenotype gaps. Reverse genomic approaches aim to analyse sequence to assign function, whereas forward genomic approaches start from a phenotype and aim to identify the underlying genotype responsible. Major Conclusions: Comparative genomic approaches, pioneered in budding yeasts, have resulted in dramatic improvements in our understanding of the function of both genes and regulatory sequences. Analogous studies in other systems, including humans, demonstrate the ubiquity of comparative genomic approaches. Recently, forward genomic approaches, exploiting natural variation within yeast populations, have started to offer powerful insights into how genotype influences phenotype and even the ability to predict phenotypes. General Significance: Comparative genomic experiments are defining the fundamental rules that govern complex traits in natural populations from yeast to humans. This article is part of a Special Issue entitled Systems Biology of Microorganisms. [Copyright &y& Elsevier]