bioRxiv preprint doi: https://doi.org/10.1101/2021.07.15.452459; this version posted July 15, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Authors: Noelia Pérez-Pereiraa, Armando Caballeroa and Aurora García-Doradob 2 Article title: Reviewing the consequences of genetic purging on the success of rescue 3 programs 4 5 6 a Centro de Investigación Mariña, Universidade de Vigo, Facultade de Bioloxía, 36310 Vigo, 7 Spain. 8 9 b Departamento de Genética, Fisiología y Microbiología, Universidad Complutense, Facultad 10 de Biología, 28040 Madrid, Spain. 11 12 13 Corresponding author: Aurora García-Dorado. Departamento de Genética, Fisiología y 14 Microbiología, Universidad Complutense, Facultad de Biología, 28040 Madrid, Spain. 15 Email address: [email protected] 16 17 ORCID CODES: 18 Noelia Pérez-Pereira: 0000-0002-4731-3712 19 Armando Caballero: 0000-0001-7391-6974 20 Aurora García-Dorado: 0000-0003-1253-2787 21 22 23 24 25 26 27 28 29 30 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.07.15.452459; this version posted July 15, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 31 DECLARATIONS: 32 Funding: This work was funded by Agencia Estatal de Investigación (AEI) (PGC2018- 33 095810-B-I00 and PID2020-114426GB-C21), Xunta de Galicia (GRC, ED431C 2020-05) 34 and Centro singular de investigación de Galicia accreditation 2019-2022, and the European 35 Union (European Regional Development Fund - ERDF), Fondos Feder “Unha maneira de 36 facer Europa”. N.P.-P. is funded by a predoctoral (FPU) grant from Ministerio de Educación, 37 Cultura y Deporte (Spain). 38 Conflicts of interest/Competing interests: Not applicable 39 Ethics approval: Not applicable 40 Consent to participate: Not applicable 41 Consent for publication: All authors have approved the manuscript for publication 42 Availability of data and material: Not applicable 43 Code availability: Codes will be available at GitHub address 44 https://github.com/noeliaperezp/Genetic_Rescue 45 46 47 48 2 bioRxiv preprint doi: https://doi.org/10.1101/2021.07.15.452459; this version posted July 15, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 49 Abstract 50 51 Genetic rescue is increasingly considered a promising and underused conservation strategy to 52 reduce inbreeding depression and restore genetic diversity in endangered populations, but the 53 empirical evidence supporting its application is limited to a few generations. Here we discuss 54 on the light of theory the role of inbreeding depression arising from partially recessive 55 deleterious mutations and of genetic purging as main determinants of the medium to long- 56 term success of rescue programs. This role depends on two main predictions: (1) The 57 inbreeding load hidden in populations with a long stable demography increases with the 58 effective population size; and (2) After a population shrinks, purging tends to remove its 59 (partially) recessive deleterious alleles, a process that is slower but more efficient for large 60 populations than for small ones. We also carry out computer simulations to investigate the 61 impact of genetic purging on the medium to long term success of genetic rescue programs. 62 For some scenarios, it is found that hybrid vigor followed by purging will lead to sustained 63 successful rescue. However, there may be specific situations where the recipient population is 64 so small that it cannot purge the inbreeding load introduced by migrants, which would lead to 65 increased fitness inbreeding depression and extinction risk in the medium to long term. In 66 such cases, the risk is expected to be higher if migrants came from a large non-purged 67 population with high inbreeding load, particularly after the accumulation of the stochastic 68 effects ascribed to repeated occasional migration events. Therefore, under the specific 69 deleterious recessive mutation model considered, we conclude that additional caution should 70 be taken in rescue programs. Unless the endangered population harbors some distinctive 71 genetic singularity whose conservation is a main concern, restoration by continuous stable 72 gene flow should be considered, whenever feasible, as it reduces the extinction risk compared 73 to repeated occasional migration and can also allow recolonization events. 74 75 76 77 78 Keywords: Migration; gene flow; reconnection; inbreeding depression; population 79 extinction. 80 81 82 3 bioRxiv preprint doi: https://doi.org/10.1101/2021.07.15.452459; this version posted July 15, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 83 Genetic rescue is the reduction of the extinction probability of endangered populations 84 through the introduction of migrant individuals. Genetic rescue programs have been 85 successful in multiple occasions (Vilà et al. 2003; Fredrickson et al. 2007; Johnson et al. 86 2010; Åkesson et al. 2016; Weeks et al. 2017; Hasselgren et al. 2018; Ralls et al. 2020), and 87 are considered a promising strategy in Conservation Biology (Waller 2015; Tallmon 2017). 88 However, most information on their consequences refer to a few generations (usually one or 89 two, rarely six, Whiteley et al. 2015). Furthermore, concern has been raised by the extinction 90 of the Isle Royale wolves population, where the genetic contribution of a single migrant wolf 91 from the large mainland population quickly spread in the resident population thanks to the 92 breeding vigor of its offspring, possibly causing an increase in inbreeding and an associated 93 fitness decline that triggered population extirpation (Hedrick et al. 2014, 2017, 2019). 94 Therefore, despite the multiple studies supporting the practice of genetic rescue (Frankham 95 2015; Kolodny et al. 2019), its consequences in the medium to long term remain uncertain 96 (Hedrick and Fredrickson 2010; Hedrick and García-Dorado 2016; Bell et al. 2019; Kyriazis 97 et al. 2020; Ralls et al. 2020). Here we review the main theoretical aspects behind the impact 98 of inbreeding depression and purging on the long-term success of rescue programs and carry 99 out computer simulations to evaluate the predicted outcome of these programs under some 100 specific scenarios. 101 102 Some background on purging and on its role during genetic rescue 103 From the genetic point of view, the main determinant of early future extinction of small 104 endangered populations is the inbreeding depression of fitness (O’Grady et al. 2006; 105 Allendorf et al. 2013; Frankham et al. 2014). This is due to the expression, as inbreeding 106 accumulates, of the initial inbreeding load B, often interpreted in terms of lethal equivalents 107 (Morton et al., 1956). Here we deal with the inbreeding load B ascribed to the recessive 108 deleterious component of many rare detrimental alleles that remains hidden in the 109 heterozygous condition in a non-inbred population (see, e.g., Caballero 2020, Chap. 8), and 110 we do not consider the possible inbreeding load ascribed to overdominance. According to 111 theory, in stable populations the inbreeding load is expected to be larger for populations with 112 larger effective size N (see Eq. 13 in García-Dorado 2007), the increase being much more 113 dramatic for more recessive deleterious alleles (García-Dorado 2003; Hedrick and García- 114 Dorado 2016). Thus, a historically large population can be genetically healthy in the sense of 4 bioRxiv preprint doi: https://doi.org/10.1101/2021.07.15.452459; this version posted July 15, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 115 showing a high average fitness but, still, its individuals are expected to be heterozygous for 116 many rare (partially) recessive deleterious alleles. 117 Due to the reduction of N in an endangered population, both drift (the dispersion of gene 118 frequencies due to random sampling of alleles) and inbreeding (the increase in homozygosis in 119 the offspring of related individuals) increase through generations. Inbreeding increases the 120 expression of recessive deleterious effects in homozygosis, which produces inbreeding 121 depression but also triggers an increase of selection against the deleterious alleles known as 122 genetic purging. The process is described by the Inbreeding-Purging model (IP model in 123 García-Dorado 2012), according to which the fitness expected by generation t (Wt) after a 124 reduction of N is predicted as in the classical Morton’s et al. (1956) model, but replacing 125 Wright’s inbreeding coefficient F with a purged inbreeding coefficient g that is weighed by the 126 ratio qt /q0, where q0 is the frequency of the deleterious allele in the original non-inbred 127 population and qt is the corresponding value expected from purging by generation t: 128 129 Wt = W0 exp(–Bgt) , (1) 130 131 where W0 and B are, respectively, the expected fitness and the inbreeding load in the initial non 132 -inbred population, and where gt can be predicted as a function of the effective population size 133 N and of the recessive component of the deleterious effects, i.e., the purging coefficient d 134 which, for a given homozygous effect s and dominance coefficient h, amounts d = s(1 – 2h)/2. 135 Thus, B is the sum of 2d(1 – q0)q0 over all the sites with segregating deleterious alleles. 136 Similarly, the corresponding inbreeding load at generation t (Bt) can be predicted as 137 Bt = B gt (1 – Ft) / Ft , (2) 138 which accounts for the joint reduction of the inbreeding load ascribed to drift and purging, that 139 is faster than under drift alone.