Inbreeding depression, the reduction of fitness caused by inbreeding, is a nearly universal phenomenon that depends on past mutation, selection, and genetic drift. Recent estimates suggest that its ...impact on individual fitness is even greater than previously thought. Genomic information is contributing to its detection and can enlighten important aspects of its genetic architecture. In natural populations, purging and genetic rescue mitigate fitness decline during inbreeding periods, and might be critical to population survival, thus, both mechanisms should be considered when assessing extinction risks. However, deliberate purging and genetic rescue involve considerable risk in the short and medium term, so that neither appears to be a panacea against high inbreeding depression.
Inbreeding is being estimated using genomic approaches in many more species that do not have pedigrees.
Pedigree inbreeding is being used in combination with genomic estimation of relationships. This partnering provides insight to what the pedigree has missed, such as inbred or related founders and inbreeding before the pedigree was initiated.
Specific loci determining inbreeding depression are being found using various approaches, such as candidate loci, homozygosity mapping or genome wide association, particularly for variants with large effects.
Inbreeding depression, purging and genetic rescue are recognized as essential elements to be considered in conservation programs, and genomic monitoring of genetic rescue and purging are being used or considered to plan and monitor management.
Meiotic rescue is a well-known phenomenon but little is known about live births after oocyte rescue, because of the shortage of data on PB biopsy. PGT-A has been performed for many years to increase ...the chance of pregnancy, especially in older women. Embryo aneuploidy is a major cause of pregnancy failure and is largely of maternal meiotic origin (>95%), with the risk increasing exponentially from approximately 35 years of age. Molecular analysis of polar bodies provides indirect assessment of an oocyte's chromosomal status by determining whether the chromosomes correctly segregated during meiosis I and II. In about one third of cases, missegregation of one or two chromosomes in meiosis I can be rescued in meiosis II, leading to a euploid oocyte. We present two cases of healthy babies born after single and double chromosome-rescued oocytes
A 42- (case 1) and a 44-year old woman (case 2) underwent ART treatment with PGT-A PB, after histories of 3 and 2 prior ART failures respectively. Both couples underwent ICSI with first and second PB biopsy and comprehensive chromosome analysis by Array-CGH. The mechanisms leading to missegregation in PB1 and PB2 (nondisjunction or premature separation of sister chromatids (PSSC)) were analysed using chromosome-specific STRs.
Case 1: a single euploid fertilized oocyte was transferred, after double rescue of chromosomes 3 and 18 (PB1 -3, -18; PB2: +3, +18) at day 2, resulting in a singleton pregnancy. Case 2: a single euploid fertilized oocyte was transferred after rescue of chromosome 16 (PB1: -16; PB2:+16) at day 3. In case 1, the aneuploidy of chromosomes 3 and 18 in the first PB was caused by PSSC followed by the extrusion of 2 homologous chromosomes in the second PB. In case 2, chromosome 16 underwent PSSC and extrusion of a single chromatid in PB1, followed by nondisjunction in meiosis II and extrusion of two sister chromatids in PB2. In both cases, the rescued oocyte was the only euploid oocyte out of 12 retrieved and they were competent for generating a pregnancy. The two women gave birth at term to healthy babies (a girl of 3280 g and a boy of 3500 g). To our knowledge, this is the first report of healthy births after a multiple chromosomally-rescued oocyte.
PGT-A of PBs is a valid method with the limitation of detecting only maternal aneuploidies and so is appropriate for screening of older women. Analysis of the 2 polar bodies by aCGH is valuable not only for aneuploidy screening in ART for older women, but also to understand the mechanisms leading to missegregation and rescue in oocytes.
Biodiversity is under threat worldwide. Over the past decade, the field of population genomics has developed across nonmodel organisms, and the results of this research have begun to be applied in ...conservation and management of wildlife species. Genomics tools can provide precise estimates of basic features of wildlife populations, such as effective population size, inbreeding, demographic history and population structure, that are critical for conservation efforts. Moreover, population genomics studies can identify particular genetic loci and variants responsible for inbreeding depression or adaptation to changing environments, allowing for conservation efforts to estimate the capacity of populations to evolve and adapt in response to environmental change and to manage for adaptive variation. While connections from basic research to applied wildlife conservation have been slow to develop, these connections are increasingly strengthening. Here we review the primary areas in which population genomics approaches can be applied to wildlife conservation and management, highlight examples of how they have been used, and provide recommendations for building on the progress that has been made in this field.
Genetic rescue to the rescue Whiteley, Andrew R.; Fitzpatrick, Sarah W.; Funk, W. Chris ...
Trends in ecology & evolution (Amsterdam),
January 2015, 2015-Jan, 2015-01-00, 20150101, Volume:
30, Issue:
1
Journal Article
Peer reviewed
•Genetic rescue is difficult to detect at the population level.•Recent studies show genetic rescue is a more powerful tool than has been appreciated.•Genomics provide a useful way to advance genetic ...rescue research and application.
Genetic rescue can increase the fitness of small, imperiled populations via immigration. A suite of studies from the past decade highlights the value of genetic rescue in increasing population fitness. Nonetheless, genetic rescue has not been widely applied to conserve many of the threatened populations that it could benefit. In this review, we highlight recent studies of genetic rescue and place it in the larger context of theoretical and empirical developments in evolutionary and conservation biology. We also propose directions to help shape future research on genetic rescue. Genetic rescue is a tool that can stem biodiversity loss more than has been appreciated, provides population resilience, and will become increasingly useful if integrated with molecular advances in population genomics.
Genetic rescue – ameliorating inbreeding depression and restoring genetic diversity of inbred populations through gene flow - is valuable in wildlife conservation. Empirically validated ...recommendations for genetic rescue supported by evolutionary genetics theory advise maximizing genetic diversity in target populations. Instead, recent papers based on genomic studies of island foxes, Isle Royal wolves, and simulation modeling claim it would be preferable to minimize introduction of harmful variation by avoiding genetic rescue altogether or by selecting partially-inbred sources presumed to have fewer harmful alleles. We examined the assertions and evidence underlying these new recommendations. The claim that long-term persistence of a few small inbred populations invalidates the small population paradigm commits the survivorship fallacy by ignoring population extinctions through inbreeding. The claim that island foxes show no inbreeding depression conflicts with elevated levels of putatively harmful alleles, low fecundity, and island-specific disease susceptibilities. The claim that the history of Isle Royale wolves represents likely outcomes of genetic rescues using immigrants from larger source populations is invalid: the unplanned addition of a single male to an inbred population capped at ~25 individuals does not represent sound genetic rescue. The simulations in Robinson et al. (2018, 2019) and Kyriazis et al. (2019 pre-print) apply several unrealistic assumptions and parameter distributions that disfavor large, outbred sources for genetic rescue. Accordingly, the simulations' conclusions conflict profoundly with those of >120 meta-analysed real datasets, and do not overturn current empirically validated recommendations to maximize genetic diversity in the target population.
•Inbreeding and loss of gene diversity are unavoidable in small isolated populations and increase extinction risks•Such populations can be often be rescued by gene flow from another population (genetic rescue)•Gene flow from genetically diverse populations is better at reversing genetic erosion than that from small populations•Proposals to minimize introduction of harmful variation are based on unrealistic simulations that contradict real-life outcomes•Maximizing genetic diversity in the target population is the best current strategy to improve fitness and ability to evolve
Additive genetic variance (VA) reflects the potential for evolutionary shifts and can be low for some traits or populations. High VA is critical for the conservation of threatened species under ...selection to facilitate adaptation. Theory predicts tight associations between population size and VA, but data from some experimental models, and managed and natural populations do not always support this prediction. However, VA comparisons often have low statistical power, are undertaken in highly controlled environments distinct from natural habitats, and focus on traits with limited ecological relevance. Moreover, investigations of VA typically fail to consider rare alleles, genetic load, or linkage disequilibrium, resulting in deleterious effects associated with favored alleles in small populations. Large population size remains essential for ensuring adaptation.
The importance of small population size in limiting adaptive potential is reinforced.
Estimates of genetic variance across populations tend to be imprecise.
Genomic data highlight linkage, load, and rare alleles in population size issues.
Long-term conservation maintaining adaptive potential requires large populations.
Many species have fragmented distribution with small isolated populations suffering inbreeding depression and/or reduced ability to evolve. Without gene flow from another population within the ...species (genetic rescue), these populations are likely to be extirpated. However, there have been only ~ 20 published cases of such outcrossing for conservation purposes, probably a very low proportion of populations that would potentially benefit. As one impediment to genetic rescues is the lack of an overview of the magnitude and consistency of genetic rescue effects in wild species, I carried out a meta‐analysis. Outcrossing of inbred populations resulted in beneficial effects in 92.9% of 156 cases screened as having a low risk of outbreeding depression. The median increase in composite fitness (combined fecundity and survival) following outcrossing was 148% in stressful environments and 45% in benign ones. Fitness benefits also increased significantly with maternal ΔF (reduction in inbreeding coefficient due to gene flow) and for naturally outbreeding versus inbreeding species. However, benefits did not differ significantly among invertebrates, vertebrates and plants. Evolutionary potential for fitness characters in inbred populations also benefited from gene flow. There are no scientific impediments to the widespread use of outcrossing to genetically rescue inbred populations of naturally outbreeding species, provided potential crosses have a low risk of outbreeding depression. I provide revised guidelines for the management of genetic rescue attempts.
See also the Perspective by Waller
Restoring gene flow into small, isolated populations can alleviate genetic load and decrease extinction risk (i.e., genetic rescue), yet gene flow is rarely augmented as a conservation strategy. Due ...to this discrepancy between opportunity and action, a recent call was made for widespread genetic rescue attempts. However, several aspects of augmenting gene flow are poorly understood, including the magnitude and duration of beneficial effects and when deleterious effects are likely to occur. We discuss the remaining uncertainties of genetic rescue in order to promote and direct future research and to hasten progress toward implementing this potentially powerful conservation strategy on a broader scale.
Genetic rescue has helped prevent the extinction of several populations, yet augmented gene flow is rarely used as a conservation strategy.Recent calls have been made for a paradigm shift in the conservation of small, isolated populations away from managing populations in isolation and toward widespread restoration of gene flow.Several aspects of genetic rescue remain poorly understood.Genetic rescue is inherently an eco-evolutionary process, and successful genetic rescue attempts have been part of comprehensive conservation plans that consider habitat, life history, and genetics.Genomics is being increasingly used in the implementation and monitoring of genetic rescue attempts.
Follicle-stimulating hormone (FSH) is a gonadotrope-derived heterodimeric glycoprotein. Both the common α- and hormone-specific β subunits contain Asn-linked N-glycan chains. Recently, ...macroheterogeneous FSH glycoforms consisting of β-subunits that differ in N-glycan number were identified in pituitaries of several species and subsequently the recombinant human FSH glycoforms biochemically characterized. Although chemical modification and in vitro site-directed mutagenesis studies defined the roles of N-glycans on gonadotropin subunits, in vivo functional analyses in a whole-animal setting are lacking. Here, we have generated transgenic mice with gonadotrope-specific expression of either an HFSHBWT transgene that encodes human FSHβ WT subunit or an HFSHBdgc transgene that encodes a human FSHβAsn7Δ 24Δ double N-glycosylation site mutant subunit, and separately introduced these transgenes onto Fshb null background using a genetic rescue strategy. We demonstrate that the human FSHβAsn7Δ 24Δ double N-glycosylation site mutant subunit, unlike human FSHβ WT subunit, inefficiently combines with the mouse α-subunit in pituitaries of Fshb null mice. FSH dimer containing this mutant FSHβ subunit is inefficiently secreted with very low levels detectable in serum. Fshb null male mice expressing HFSHBdgc transgene are fertile and exhibit testis tubule size and sperm number similar to those of Fshb null mice. Fshb null female mice expressing the mutant, but not WT human FSHβ subunit-containing FSH dimer are infertile, demonstrate no evidence of estrus cycles, and many of the FSH-responsive genes remain suppressed in their ovaries. Thus, HFSHBdgc unlike HFSHBWT transgene does not rescue Fshb null mice. Our genetic approach provides direct in vivo evidence that N-linked glycans on FSHβ subunit are essential for its efficient assembly with the α-subunit to form FSH heterodimer in pituitary. Our studies also reveal that N-glycans on FSHβ subunit are essential for FSH secretion and FSH in vivo bioactivity to regulate gonadal growth and physiology.
•In vivo functions of N-linked glycans on human FSHβ subunit tested in mouse models.•HFSHBWT and HFSHBdgc (encodes a N-glycosylation mutant hFSHβ subunit) mice are generated on an Fshb−/− background.•HFSHB transgenes are targeted to pituitary and specifically expressed in gonadotropes.•HFSHBdgc encoded double N-glycosylation mutant human FSHβ subunit inefficiently assembles with mouse α-subunit.•Double N-glycosylation mutant human FSHβ subunit containing FSH dimer is inefficiently secreted and does not rescue Fshb−/− mice.
Assisted gene flow (AGF) between populations has the potential to mitigate maladaptation due to climate change. However, AGF may cause outbreeding depression (especially if source and recipient ...populations have been long isolated) and may disrupt local adaptation to nonclimatic factors. Selection should eliminate extrinsic outbreeding depression due to adaptive differences in large populations, and simulations suggest that, within a few generations, evolution should resolve mild intrinsic outbreeding depression due to epistasis. To weigh the risks of AGF against those of maladaptation due to climate change, we need to know the species' extent of local adaptation to climate and other environmental factors, as well as its pattern of gene flow. AGF should be a powerful tool for managing foundation and resource-producing species with large populations and broad ranges that show signs of historical adaptation to local climatic conditions.
PDF
