Parent‐offspring inference in inbred populations

Genealogical relationships are fundamental components of genetic studies. However, it is often challenging to infer correct and complete pedigrees even when genome-wide information is available. For example, inbreeding can obscure genetic differences between individuals, making it difficult to even distinguish first-degree relatives such as parent-offspring from full siblings. Similarly, genotyping errors can interfere with the detection of genetic similarity between parents and their offspring. Inbreeding is common in natural, domesticated, and experimental populations and genotyping of these populations often has more errors than in human data sets, so efficient methods for building pedigrees under these conditions are necessary. Here, we present a new method for parent-offspring inference in inbred pedigrees called specific parent-offspring relationship estimation (spore). spore is vastly superior to existing pedigree-inference methods at detecting parent-offspring relationships, in particular when inbreeding is high or in the presence of genotyping errors, or both. spore therefore fills an important void in the arsenal of pedigree inference tools

Resistance to natural and synthetic gene drive systems

Scientists are rapidly developing synthetic gene drive elements intended for release into natural populations. These are intended to control or eradicate disease vectors and pests, or to spread useful traits through wild populations for disease control or conservation purposes. However, a crucial problem for gene drives is the evolution of resistance against them, preventing their spread. Understanding the mechanisms by which populations might evolve resistance is essential for engineering effective gene drive systems. This review summarizes our current knowledge of drive resistance in both natural and synthetic gene drives. We explore how insights from naturally occurring and synthetic drive systems can be integrated to improve the design of gene drives, better predict the outcome of releases and understand genomic conflict in general

Resistance to natural and synthetic gene drive systems

Scientists are rapidly developing synthetic gene drive elements intended for release into natural populations. These are intended to control or eradicate disease vectors and pests, or to spread useful traits through wild populations for disease control or conservation purposes. However, a crucial problem for gene drives is the evolution of resistance against them, preventing their spread. Understanding the mechanisms by which populations might evolve resistance is essential for engineering effective gene drive systems. This review summarizes our current knowledge of drive resistance in both natural and synthetic gene drives. We explore how insights from naturally occurring and synthetic drive systems can be integrated to improve the design of gene drives, better predict the outcome of releases and understand genomic conflict in general

Discovery of a selfish supergene's dispersal phenotype in house mice Mus musculus domesticus

The organism and its genome are a remarkable cooperative achievement of billions of DNA bases that work together. Natural selection has shaped the genome into cooperation by generally favoring those genomes that work well as a whole, rather than resembling collections of genes that do not produce anything greater than the sum of their parts. But what seems perfectly harmonious is actually the site of an ever-lasting struggle over transmission from one generation to the next. This struggle is only contained by the benefits that cooperation accrues for each genetic element. In organisms with two sets of chromosomes, each gene is only transmitted to half of all offspring, but from the perspective of the gene, it would be much preferable if it was transmitted to all. Consequently, some genes manipulate that process and increase their own transmission to the detriment of the genes that are thereby transmitted less often as well as the rest of the genome. The t haplotype in house mice is such a selfish actor in the genome of house mice that carry it. It is a collection of linked genes, a supergene, that makes up 1% of the house mouse genome. It increases its own transmission from male carriers to their offspring to over 90%, rather than the expected 50%. However, not every mouse carries the t supergene, which puzzled biologists given its increased rate of transmission. This is due to the t's two strongly disadvantageous traits. First, mice that carry the t haplotype on both chromosomes are either infertile as males or completely inviable. This immediately puts an upper limit on the frequency of the t haplotype in any population, because at a minimum not all mice can carry it on both chromosomes. However, this disadvantage alone would still allow for high frequencies of the t, but that is not what is found in nature. The second disadvantage of the t is likely a consequence of the mechanism with which it increases its own transmission. The t increases its transmission using a poison-antidote mechanism; it poisons all sperm of its carrier, but there is an antidote in the sperm that carry the t, thus only sperm that do not carry the t should be harmed. However, t-carrying sperm are negatively impacted by this poison-antidote mechanism,as well, but to a lesser degree. The damage caused by this mechanism comes into full effect when t-carrying males are mating with females who also mate with other males in the same estrus cycle. This constellation creates competition between the sperm of the different males that mated with the female. Insperm competition, t-carrying males are much less successful in fertilizing the female than males who do not carry the t. This second disadvantage is so strong that it could explain the very low frequencies of the t in the wild. In very dense populations, where sperm competition is more common due to more matings per estrus cycle, thet can even go extinct, opening the question why the t has not gone extinct completely. In this thesis, I am introducing, testing, and verifying the hypothesis that the t haplotype increases the probability with which t-carriers emigrate from populations to settle elsewhere, a process known as dispersal. Dispersal is a dangerous behavior, which is why the costs and benefits of it have shaped individual propensity to disperse over evolutionary time. Thus, a deviation from "normal" odds of dispersal could be against the interest of the organism as a whole. In Chapter 1, I introduce the reader to the broader picture of the conflict between genes within an individual's genome. In Chapter 2, I describe the hypothesis that t-carriers should be more dispersive than mice who do not carry the t, because this way the t is better equipped to avoid populations in which its disadvantageous traits are most pronounced. I tested this hypothesis using an intensively studied population of house mice and found an increased number of t-carrying mice emigrating from the population. In Chapter 3, I investigate the evolution of increased dispersal more formally using computer simulations. I find that the two disadvantageous traits of the t, inviability when carried on both chromosomes and poor performance in sperm competition with other males, indeed select for increased dispersal. However, the increased transmission alone is not sufficient to evolve increased dispersal. In Chapter 4, I verify the hypothesis using controlled experimental setups and I furthermore find that t-carriers are also heavier, more likely to disperse at higher weights, and more prone to explore unknown areas than mice who do not carry the t, which are all traits that could be beneficial for mice who are more likely to disperse. I conclude that the t haplotype appears to produce a remarkable dispersal phenotype in the mice that carry the t, which is a rare finding that should combine very well with the t's increased transmission. Finally, in Chapter 5, I provide an outlook on work towards understanding the genetic basis of the t's influence on dispersal. I describe a novel adaptation of a statistical method that allows us to gain insights into the genome sequences of mice much more cost-efficientlyt han what used to be possible, which will enable us to study the genetic basis of dispersal in house mice

Experiments confirm a dispersive phenotype associated with a natural gene drive system

Meiotic drivers are genetic entities that increase their own probability of being transmitted to offspring, usually to the detriment of the rest of the organism, thus ‘selfishly’ increasing their fitness. In many meiotic drive systems, driver-carrying males are less successful in sperm competition, which occurs when females mate with multiple males in one oestrus cycle (polyandry). How do drivers respond to this selection? An observational study found that house mice carrying the t haplotype, a meiotic driver, are more likely to disperse from dense populations. This could help the t avoid detrimental sperm competition, because density is associated with the frequency of polyandry. However, no controlled experiments have been conducted to test these findings. Here, we confirm that carriers of the t haplotype are more dispersive, but we do not find this to depend on the local density. t-carriers with above-average body weight were particularly more likely to disperse than wild-type mice. t-carrying mice were also more explorative but not more active than wild-type mice. These results add experimental support to the previous observational finding that the t haplotype affects the dispersal phenotype in house mice, which supports the hypothesis that dispersal reduces the fitness costs of the t

The t haplotype, a selfish genetic element, manipulates migration propensity in free-living wild house mice Mus musculus domesticus

Life is built on cooperation between genes, which makes it vulnerable to parasitism. However, selfish genetic elements that exploit this cooperation can achieve large fitness gains by increasing their transmission unfairly relative to the rest of the genome. This leads to counter-adaptations that generate unique selection pressures on the selfish genetic element. This arms race is similar to host-parasite co-evolution. Some multi-host parasites alter the host’s behaviour to increase the chance of transmission to the next host. Here we ask if, similarly to these parasites, a selfish genetic element in house mice, the t haplotype, also manipulates host behaviour, specifically the host’s migration propensity. Variants of the t that manipulate migration propensity could increase in fitness in a meta-population. We show that juvenile mice carrying the t haplotype were more likely to emigrate from and were more often found as migrants within a long-term free-living house mouse population. This result may have applied relevance as the t has been proposed as a basis for artificial gene drive systems for use in population control

Parent-offspring inference in inbred populations

Genealogical relationships are fundamental components of genetic studies. However, it is often challenging to infer correct and complete pedigrees even when genome-wide information is available. For example, inbreeding can obfuscate genetic differences between individuals, making it difficult to even distinguish first-degree relatives such as parent-offspring from full siblings. Similarly, genotyping errors can interfere with the detection of genetic similarity between parents and their offspring. Inbreeding is common in natural, domesticated, and experimental populations and genotyping of these populations often has more errors than in human datasets, so efficient methods for building pedigrees under these conditions are necessary. Here, we present a new method for parent-offspring inference in inbred pedigrees called SPORE (Specific Parent-Offspring Relationship Estimation). SPORE is vastly superior to existing pedigree-inference methods at detecting parent-offspring relationships, in particular when inbreeding is high or in the presence of genotyping errors, or both. SPORE therefore fills an important void in the arsenal of pedigree inference tools.Author SummaryKnowing the genealogical relationships among individuals is critical for genetic analyses, such as for identifying the mutations that cause diseases or that contribute to valuable agricultural traits such as milk production. Although many tools exist for establishing pedigrees using genetic information, these tools fail when individuals are highly inbred, such as in domesticated animals, or in groups of people in which consanguineous matings are common. Furthermore, existing tools do not work well when genetic information has errors at levels observed in modern datasets. Here, we present a novel approach to solve these problems. Our method is significantly more accurate than existing tools and more tolerant of errors in the genetic data. We expect that our method, which is simple to use and computationally efficient, will be a useful tool in a diversity of settings, from the studies of human and natural populations, to agricultural and experimental settings

Carrying a selfish genetic element predicts increased migration propensity in free-living wild house mice

Life is built on cooperation between genes, which makes it vulnerable to parasitism. Selfish genetic elements that exploit this cooperation can achieve large fitness gains by increasing their transmission relative to the rest of the genome. This leads to counter-adaptations that generate unique selection pressures on the selfish genetic element. This arms race is similar to host–parasite coevolution, as some multi-host parasites alter the host’s behaviour to increase the chance of transmission to the next host. Here, we ask if, similarly to these parasites, a selfish genetic element in house mice, the t haplotype, also manipulates host behaviour, specifically the host’s migration propensity. Variants of the t that manipulate migration propensity could increase in fitness in a meta-population. We show that juvenile mice carrying the t haplotype were more likely to emigrate from and were more often found as migrants within a long-term free-living house mouse population. This result may have applied relevance as the t has been proposed as a basis for artificial gene drive systems for use in population control

Selfish migrants: How a meiotic driver is selected to increase dispersal

Meiotic drivers are selfish genetic elements that manipulate meiosis to increase their transmission to the next generation to the detriment of the rest of the genome. The t haplotype in house mice is a naturally occurring meiotic driver with deleterious traits—poor fitness in polyandrous matings and homozygote inviability or infertility—that prevent its fixation. Recently, we discovered a novel effect of t in a long-term field study on free-living wild house mice: t-carriers are more likely to disperse. To ask what known traits of the t haplotype can select for a difference in dispersal between t-carriers and wildtype mice, we built individual-based models with dispersal loci on the t and the homologous wildtype chromosomes. We allow for density-dependent expression of these loci. The t haplotype consistently evolved to increase the dispersal propensity of its carriers, particularly at high densities. By examining variants of the model that modify different costs caused by t, we show that the increase in dispersal is driven by the deleterious traits of t, disadvantage in polyandrous matings and lethal homozygosity or male sterility. Finally, we show that an increase in driver-carrier dispersal can evolve across a range of values in driver strength and disadvantages