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Pathogenic variants occurring in protein-coding regions underlie human genetic disease through various mechanisms. They can lead to a loss of function (LOF) such as in recessive conditions or in dominant conditions due to haploinsufficiency. Dominant-negative (DN) effects, counteracting the activity of the normal gene-product, and gain of function (GOF) are also mechanisms driving dominance. Here, I discuss a few papers on these specific mechanisms. In short, there is accumulating evidence pointing to differences between LOF versus non-LOF variants (DN and GOF). The latter are thought to have milder effects on protein structure and, as expected, DN variants are enriched at protein interfaces. This tendency to cluster in 3D space can help improve the ability of computational tools to predict the pathogenicity of DN variants, which is currently a challenging issue. More recent results support the hypothesis whereby cotranslational assembly of macromolecular complexes can buffer deleterious consequences of variants that would otherwise lead to DN effects (DNEs). Indeed, subunits the variants of which are responsible for DNEs tend to elude cotranslational assembly, thus poisoning complexes involving wild-type subunits. The constraints explaining why the buffering of DNEs is not universal require further investigation., (© 2023 The Authors. BioEssays published by Wiley Periodicals LLC.)

With the ever-increasing lifespan along with societal changes, women can marry and procreate later than in previous centuries. However, pathogenic genetic variants segregating in the population can lead to female subfertility or infertility well before the average age of normal menopause, leading to counter-selection of such deleterious alleles. In reviewing this field, we speculate that a logical consequence would be the later occurrence of menopause and the extension of women's reproductive lifespan. We illustrate this point with a simple model that applies to other variants that contribute to female infertility, including epigenetic variation. We also consider the effect of medical interventions and lifestyle., (© 2021 Wiley Periodicals LLC.)

Mutations in human genes encoding transcription factors are often dominant because one active allele cannot ensure a normal phenotype (haploinsufficiency). In other instances, heterozygous mutations of two genes are required for a phenotype to appear (combined haploinsufficiency). Here, we explore with models (i) the basis of haploinsufficiency and combined haploinsufficiency owing to mutations in transcription activators, and (ii) how the effects of such mutations can be amplified or buffered by subsequent steps in a transcription cascade. We propose that the non-linear (sigmoidal) response of transcription to the concentration of activators can explain haploinsufficiency. We further show that the sigmoidal character of the output of a cascade increases with the number of steps involved, the settings of which will determine the buffering or enhancement of the effects of a decreased concentration of an upstream activator. This exploration provides insights into the bases of compensatory mutations and on interloci interactions underlying oligogenic inheritance patterns., (© 2014 WILEY Periodicals, Inc.)

Testis determination in most mammals is regulated by a genetic hierarchy initiated by the SRY gene. Early ovarian development has long been thought of as a default pathway switched on passively by the absence of SRY. Recent studies challenge this view and show that the ovary constantly represses male-specific genes, from embryonic stages to adulthood. Notably, the absence of the crucial ovarian transcription factor FOXL2 (alone or in combination with other factors) induces a derepression of male-specific genes during development, postnatally and, even more interestingly, during adulthood. Strikingly, in the adult, targeted ablation of Foxl2 leads to a molecular transdifferentiation of the supporting cells of the ovary, which acquire cytological and transcriptomic characteristics of the supporting cells of the testes. These studies bring many answers to the field of gonadal determination, differentiation and maintenance, but also open many questions.

Positional cloning of the quantitative trait locus (QTL) still encounters numerous difficulties, which explains why thousands of QTL have been mapped, while only a few have been identified at the molecular level. Here, we focus on a specific mapping tool that exists in plant and animal model species: interspecific recombinant congenic strains (IRCSs) or interspecific nearly isogenic lines (NILs). Such panels exhibit a much higher sequence diversity than intraspecific sets, thus enhancing the contrasts between phenotypes. In animals, it allows statistical significance to be reached even when using a limited number of individuals. Therefore, we argue that interspecific resources may constitute a major genetic tool for positional cloning and for understanding some bases of speciation mechanisms.

Expression of most genes is regulated by the interaction of multiple transcription factors with cis-regulatory sequences. Many studies have focused on how changes in promoters and enhancers alter gene expression and phenotype. Recently, Hare et al., using elegant wet and computational approaches uncovered a series of enhancers driving the expression of the even-skipped gene in scavenger flies (Sepsidae). Despite the strong sequence divergence between the enhancers in sepsids and drosophilids, they lead to remarkably similar patterns of gene expression in transgenic Drosophila embryos. This can be explained by the existence of intra-enhancer compensatory mutations and the presence of overlapping/near binding sites for activators and repressors.

Sharp sigmoidal transitions of transcription in response to morphogenetic gradients are often involved in the generation of boundaries during development. Here we explore two simple models of transcription that generate sigmoidal outputs. Specifically, we analyse the case of a promoter responding to a single type of activator. We then consider a model where an activator and an inhibitor, distributed as two gradients with opposite slopes, act competitively on the same promoter. This system can produce a sharper response than that obtained with a promoter with the same number of binding sites responding to a similar gradient of activator alone. We also explore how these systems buffer the effect of variations in the dosage of the morphogens. Our results highlight how non-linearities can be a source of robustness and the crucial role of the inhibitor in the generation of a sharp and robust response., (Copyright 2006 Wiley Periodicals, Inc.)

The rapid generation of new shapes observed in the living world is the result of genetic variation, especially in "morphological" developmental genes. Many of these genes contain coding tandem repeats. Fondon and Garner have shown that expansions and contractions of these repeats are associated with the great diversity of morphologies observed in the domestic dog, Canis familiaris. In particular, they found that the repeat variations in two genes were significantly associated with changes in limb and skull morphology. These results open the possibility that such a mechanism contributes to the diversity of life.

The focus of this essay is the phenomenon of haploinsufficiency (HI), a manifestation of genetic dominance that arises when only one allele of a normally diploid locus is present. Specifically, I examine the nature of HI for transcription factor genes. Although the concept of HI applies to many such genes, there is a potentially large variety of mechanisms that underlie it. Even when the phenomenon is linked in all cases to reduced absolute gene expression levels, there are several well-documented cases where the explanation is not reduced expression per se but altered stoichiometry. I will discuss the notion of haploimbalance in general and evaluate the property of transcriptional synergy within the context of HI. This kind of non-linear behaviour can probably explain a large proportion of the cases of HI, as well as the variability in most HI phenotypes and the fact that several factors in the same pathway may be dosage sensitive. For the sake of generality, a theoretical analysis of simple non-linear HI systems is also attempted. This article is certainly another preliminary exploration of the complex matters of HI, which remain an intellectual challenge from many points of view., (Copyright 2002 Wiley Periodicals, Inc.)