Inbreeding intensifies sex- and age- dependent disease in a wild mammal

(cid:400)(cid:314) The mutation accumu(cid:1140)ation theory of senescence predicts that age(cid:330)re(cid:1140)ated dete rioration of fitness can be exaggerated when inbreeding causes homozygosity for de(cid:1140)eterious

However there is scant evidence to date for inks among age disease inbreeding and sex in a sing e natura popu ation Using eco ogica and epidemio ogica data from a ong term ongitudina fie d study we show that in wi d European badgers Meles meles exposed natura y to bovine tubercu osis bTB inbreeding measured as mu ti ocus homozygosity intensifies a positive corre ation between age and evidence of progressed infection measured as an antibody response to bTB but on y among fema es Ma e badgers suffer a steeper re ationship between age and progressed infection than fema es with no inf uence of inbred status We found no ink between inbreeding and the incidence of progressed infection during ear y ife in either sex Our findings high ight an age re ated increase in the impact of inbreeding on a fitness re evant trait disease state among fema es This re ationship is consistent with the predictions of the mutation accumu ation theory of senescence but other mechanisms cou d a so p ay a ro e For examp e ate ife dec ines in condition arising through mechanisms other than mutation accumu ation might have increased the magnitude of inbreeding depression in ate ife Whichever mechanism causes the observed patterns we have shown that inbreeding can inf uence age dependent patterns of disease and by extension is ike y to affect the magnitude and timing of the ate ife dec ines in components of fitness that characterise senescence Better understanding of sex specific inks between inbreeding disease and ageing provides insights into popu ation eve pathogen dynamics and cou d inf uence management strategies for wi d ife reser-

voirs of zoonotic disease
This is an open access artic e under the terms of the Creative Commons Attribution License which permits use distribution and reproduction in any medium provided the origina work is proper y cited Crown copyright Journa of Anima Eco ogy British Eco ogica Society We investigate the re ationship between inbreeding age sex and disease status using data from a ong term study of badgers natura y exposed to M. bovis infection We predict that individua s with higher inbreeding coefficients wi be more ike y to express antibody responses to infection indicative of progressed disease We further predict based on the mutation accumu ation mode of ageing Medawar that this ink between inbreeding coefficients and progressed disease wi intensify with age We a so propose that this ink between inbreeding and age dependent patterns of infection wi differ between ma es and fema es but it is difficu t to predict which sex wi suffer age dependent progression more acute y or in which sex it wi be most easi y detected

| Badger samp ing and TB diagnostic tests
A data used in these ana yses were co ected from the capture mark recapture study of a wi d popu ation of badgers at We tested for heterogeneity in homozygosity among badger socia groups and regressed group eve homozygosity against group eve disease incidence using mixed effects mode s with incidence as a binomia response and year as a random effect |

RESULTS
The censored dataset comprised capture events from to of individua exposed badgers of known age The ike ihood of detecting an antibody response to bTB here considered indicative of progressed infection see above increased with age This resu t he d whether age was mode ed as a continuous

FIGURE
The re ationship between badger age and the ike ihood of detection of antibody response to Mycobacterium bovis intensifies with increasing va ues of marker wide homozygosity among fema es a but not ma es b Data are co oured by deviation from average homozygosity measured in ha f standard deviations from the mean from dark grey most heterozygous individua s standard deviations from the mean to pa e grey most homozygous individua s standard deviations from the mean and sized proportiona y to the number of data points for each age homozygosity combination Fitted ines are from sex specific genera ised mixed mode s of antibody response against sex age and homozygosity inc uding badger year and socia group as random effects In the ma es on y mode there is no significant interaction between age and homozygosity and no main effect of homozygosity Co ours of fitted ines fo ow the co our ramp of data points from dark grey most heterozygous individua s to pa e grey most homozygous individua s   p Va ues from a series of individua mode s to assess the strength of association between antibody responses to Mycobacterium bovis infection and homozygosity at each marker ocus in badgers from Woodchester Park genera effect hypothesis for inbreeding depression in which neutra marker oci are corre ated with genomewide heterozygosity We propose a combination of oca and genera impacts of inbreeding depression in this case Genera and oca effects represent two ends of a spectrum and this popu ation ies somewhere a ong the sca e Ba oux et a In the absence of experimenta cha enge and without know edge of the timing of exposure to infection we cannot tease apart the exposure resistance and to erance mechanisms that drive the age dependence of progressed disease detected here The pattern cou d ref ect increases with age in the cumu ative probabi ity of a a naive individua having been exposed to the disease and or b an exposed individua having experienced disease progression A ternative y exposure resistance and to erance might themse ves change with age making them tru y senescent drivers of age dependent disease This means that the inf uence of inbreeding cou d be on age independent rates of exposure resistance or to erance or on the pattern of senescence in these rates Inbreeding cou d inf uence rates of exposure to disease via changes in behaviour or condition It is a so possib e that age re ated dec ines in components of immunity as previous y  Average eve s of marker wide homozygosity varied significant y among badger groups barp ot a derived from mixed effects mode of homozygosity regressed against socia group with year as random effect but there was no significant re ationship between the preva ence of antibody response to bTB infection and average homozygosity of the socia group scatterp ot b more prone to forming socia inks with members of other groups making them of particu ar importance in disease transmission be-