This post is going to be a little melodramatic, but I hope that despite all the reading on inbreeding depression, you won’t get depressed.
As the media finally started feeding us all the catastrophic news about the impact of global warming on the environment – every month being reported as the warmest in history, videos of melting ice sheets, and crazy graphs showing climate predictions – scientists are trying to figure out ways to prevent the worst.
Conservation biologists are probably going to be pretty busy, all these populations disappearing and becoming isolated because of changing environment and habitat fragmentation. Isolated and fragmented populations will be affected by stochastic factors, including genetic drift and inbreeding. The problem is that some basic concepts of these processes are still not completely understood. At least not in natural populations. And with that I’ll leave the word to Fred Allendorf and his colleagues:
“Despite decades of research, we still have a limited understanding of the strength, underlying genetic mechanisms, and demographic consequences of inbreeding depression in the wild.” (Kardos et al. 2016)
The problem with studying inbreeding depression in natural populations is that until recently it required a very precise pedigree, which is quite difficult to obtain in the wild. However, the genomic revolution has entered the field of conservation biology and there are some strong advocates for leaving the pedigree-based methods behind and for transitioning to the genomic era (Kardos et al. 2015, Kardos et al. 2016).
To get this straight, I absolutely don’t mean to say that conservation biologists have been powerless until high-throughput sequencing appeared. What I mean to say is that with the kind of data we have available nowadays, we can finally answer some burning issues like the severity and impact of inbreeding depression in wild populations. No surprise then that two of the big names in conservation biology, Fred Allendorf and Phil Hedrick, both published thorough review papers on the topic last year.
These studies are an excellent source of information, containing definitions, glossaries, and explanations of the theoretical concepts and methodologies. And I’ll immediately make use of it for defining the inbreeding depression. Just to make clear what it actually is.
“Inbreeding depression: the reduction of fitness because of lower survival, mating, and/or reproduction in the progeny of related individuals compared to the progeny of unrelated individuals.” (Hedrick and Garcia-Dorado, 2016)
Individual inbreeding is measured as the probability of observing two alleles (in a diploid organism) identical-by-descent (IBD), i.e. two homologous copies of a gene originating from a single copy present in the ancestor. This probability is called inbreeding coefficient (F) and traditionally was estimated from the pedigree (Fp).
Anybody who paid attention in the Biology classes knows that all branches of a phylogenetic tree converge at some point, so the idea of related/non-related and ancestral/non-ancestral might cause a little bit of a headache, unless you read the following explanation:
“The concept of F as a parametric definition of individual inbreeding is somewhat complicated by the fact that all pairs of homologous gene copies derive from a single ancestral copy at some point in the past. There is a continuum of the “time to the most recent common ancestor” (TMRCA) for homologous loci across an individual’s genome (Speed & Balding, 2015)… Chromosome segments with very large TMRCA (e.g. hundreds to thousands of generations) tend to be very short and are more likely to contain heterozygous positions arising from mutations along one or the other of the parental lineages reaching back to the common ancestral copy.” (Kardos et al. 2016)
Technically, there is no general rule about what is a long or a short fragment, but only long fragments originating from recent ancestors are usually considered. But it’s not only time to TMRCA that influences the length of IBD, there’s also some IBD variation introduced by recombination and segregation, which cannot be captured in a pedigree. Moreover, the major limitation of a pedigree is that it can be inaccurate and usually underestimates F because of unknown relatedness.
Kardos et al. (2016) strongly argue that rather than using (Fp), we should be using marker-based measures of F, which can “range from simple estimates of individual heterozygosity to more advanced methods that use mapped loci to estimate F via identification of IBD chromosome segments as stretches of homozygous genotypes at mapped SNPs (i.e. “runs of homozygosity” [ROH]”. And there’s a growing number of studies that support their argument (Hoffman et al. 2014, Kardos et al. 2015, Huisman et al. 2016, Hedrick et al. 2016).
Isle Royale wolves and their complex relationships
Want a real-life example? How about the enigmatic Isle Royale wolves? A lot has been written about this population, which has been monitored for almost 60 years (for some reason it makes me think of the Big Brother reality show). There are only two wolves left, half-sibs and at the same time a father and daughter. Like in a really bad soap opera.
“The remaining wolves in the Isle Royal population are closely related because they are both father and daughter and half-siblings. As a result, the expected relatedness between them is 0.734 and the expected inbreeding from an offspring from them is 0.438. Further, based on our analysis here, at 31.2% of their genes they share both copies IBD, and the 95% confidence interval for the F from an offspring is from 0.311 to 0.565. In other words, as high as the expectations for these measures are, it is very likely that individuals have genomic relatedness or inbreeding values that deviate substantially from the pedigree-based expectations.” (Hedrick et al. 2016)
In other words, Fp says 0.438 while F says 0.311 to 0.565, quite a difference I would say.
The reason why I tried to highlight the gaps in our knowledge in the beginning of this post was actually related to the two freshly published papers by Phil Hedrick, which use the poor Isle Royale wolves as a model for studying inbreeding.
It’s a sad story. Wolves have inhabited Isle Royale since 1940s and have been living there in isolation. When a male wolf called Old Grey Guy (or also M93) immigrated to the island in 1997, it took the population by storm and in 2008 59.4% of the population ancestry originated from this wolf. It was probably genetic rescue at the time, but it also might have brought the Isle Royale wolves on the verge of extinction.
“…it is possible that some recessive detrimental variants with large effects were introduced by the immigration of M93. Because he came from a presumably very large population in Canada, there might not have been past purging of detrimental variation as could possibly have occurred in the much smaller Isle Royale population. The initial progeny from M93 and his mate (F99) might have had higher fitness than other wolves because some detrimental alleles accumulated in the Isle Royale population were heterozygous in these initial offspring and the success of these offspring could have increased the frequency of detrimental variants brought in by M93. With inbreeding, these detrimental alleles were subsequently expressed as homozygotes and resulted in lowered fitness.” (Hedrik et al. 2016)
And that’s why we need to understand inbreeding depression, genetic purging, and genetic rescue properly, before we start playing with saving species. A completely other set of important questions, which I haven’t even touched upon, is about the effect of inbreeding depression on fitness and long-term survival of populations (e.g. Norén et al. 2016). I think I’ll just leave this post by referring to an weirdly amusing study on inbreeding depression in the Charles Darwin’s family.
Álvarez G, Ceballos FC, Berra TM (2015) Darwin was right: inbreeding depression on male fertility in the Darwin family. Biol. J. Linn. Soc. 114, 474– 483. doi: 10.1111/bij.12433
Hedrick PW & García-Dorado A (2016) Understanding inbreeding depression, purging, and genetic rescue. Trends in Ecology and Evolution, 31(12), 940-952 doi: http://dx.doi.org/10/1016/j.tree.2016.09.005
Hedrick PW, Kardos M, Peterson RO, Vucetich JA (2016) Genomic Variation of Inbreeding and Ancestry in the Remaining Two Isle Royale Wolves. J Hered 2016 esw083. doi: 10.1093/jhered/esw083
Hoffman JI, Simpson F, David P, Rijks JM, Kuiken T, Thorne MA, Dasmahapatra KK (2014) High-throughput sequencing reveals inbreeding depression in a natural population. Proceedings of the National Academy of Sciences USA, 111, 3775–3780. doi/10.1073/pnas.1318945111
Huisman J, Kruuk LE, Ellis PA, Clutton-Brock T, Pemberton JM (2016) Inbreeding depression across the lifespan in a wild mammal population. Proceedings of the National Academy of Sciences USA, 113, 3585–3590. doi/10.1073/pnas.1518046113
Kardos M, Taylor H, Ellegren H, Luikart G, Allendorf FW (2016) Genomics advances the study of inbreeding depression in the wild. Evol Applic. doi: 10.1111/eva.12414
Kardos M, Luikart G, Allendorf FW. 2015. Measuring individual inbreeding in the age of genomics: marker-based measures are better than pedigrees. Heredity. 115:63-72. doi:10.1038/hdy.2015.17
Norén K, Godoy E, Dalén L, Meijer T, Angerbjörn A (2016) Inbreeding depression in a critically endangered carnivore. Mol Ecol, 25: 3309–3318. doi:10.1111/mec.13674