- We show that minor satellite copy number varies more than 10-fold among inbred mouse strains, whereas major satellite copy numbers span a 3-fold range. - Intriguingly, we also find that wild-caught mice harbor dramatically reduced minor satellite copy number and elevated satellite sequence heterogeneity compared to inbred strains, suggesting that. - The minor satellite region is flanked by a 234-bp major satellite repeat array that extends over ~ 2 Mb of sequence per chromosome. - 1 Significant differences in consensus centromere satellite copy number across Mus musculus. - 2, Supplementary Figure 3), we sought to further define strain, subspecies, and popula- tion variation in both major and minor satellite copy number. - We estimate between 1320 and 260,220 minor satellite copies and major. - Similarly, we estimate between 2900 and 37,240 minor satellite copies and major satellite copies in wild-caught M. - The greater number of major satellite repeats relative to minor satellite repeats is consistent with the known size differences between the major and minor satellite array in M. - We next sought to estimate the proportion of variation in both major and minor satellite copy number that is attributable to differences between inbred strains, rather than technical artifacts from library preparation and other sources of error. - Over 80% of the variance in minor satellite 31-mer frequencies is due to strain differ- ences (80.3%. - Thus, the majority of observed variation in both major and minor satellite 31-mer frequencies is due to intrinsic genomic differences between strains.. - Subspecies identity ac- counts for the majority of variation in minor satellite 31- mer frequencies (83.9% of variance. - Thus, samples with more major satellite copies do not neces- sarily have more minor satellite copies. - We focused on a subset of strains that encompass a range of estimated minor satellite copy numbers and span three principal house mouse subspecies: CAST/EiJ (M. - This ob- servation contrasts with the more uniform intensity of the minor satellite signal across all chromosomes in CAST/EiJ and PWK/PhJ (Fig. - The minor satellite CDI is lower in inbred strains (range than in wild mice (range . - musculus have minor satellite arrays that are nearly 3. - For both inbred and wild mice, the average minor satellite CDI (inbred. - musculus the minor satellite harbors appreciably higher sequence diversity than the major satellite (Fig. - Subspecies identity accounts for 39.2% of the variance in minor satellite CDI (F P <. - minor satellite: Spearman’s rho. - The similarity in minor satellite size and di- versity in inbred strain CAST/EiJ and wild-caught M. - Despite its smaller size, the minor satellite harbors more sites with at least 20% non-consensus nucleotide usage than the major sat- ellite (107 versus 79. - Estimated centromere satellite copy number and centromere diversity index for the (a) minor or (b) major satellite sequence. - In addition, position 78 exhibits more variability in the proportion of non-consensus nucleotide usage than any other minor satellite position in both inbred strains and wild-caught mice. - On average, inbred strains have lower rates of non-consensus nucleotide usage (minor satellite 2.9–. - major satellite 3.6–4.4%) compared to wild-caught mice (minor satellite 4.8–6.8%. - major satellite 5.7–6.5%).. - Phylogenetic distribution of minor satellite copy number and repeat heterogeneity. - We quantified the proportion of variation in major and minor satellite copy number and CDI that is explained by the phylogenies relating inbred strains (Fig. - Across inbred strains, the phylogenetic heritability of both minor satellite copy number ( H 2 P = 0.56. - Evidently, both measures of minor satellite variation evolve sufficiently rapidly to outpace signals of strain relatedness. - P = 0.003, major satellite copy number H 2 P = 0.98. - P = 0.003, minor satellite CDI H 2 P = 0.98. - The contrast in minor satellite H 2 P estimates between the inbred and wild-caught mice provides fur- ther support for the hypothesis that inbreeding fosters a unique setting for the evolution of centromere architecture.. - We found no significant correlation between this measure of gen- ome stability and either major or minor satellite consen- sus copy number (Supplementary Figure 7). - This result suggests (i) the absence of centromere-mediated meiotic drive in this complex population, (ii) the lack of power to detect weak drive signals, (iii) that drive is influenced by multiple genetic factors [49], or (iv) that aspects of centromere architecture other than minor satellite copy number may be critical for defining drive potential.. - Most notably, minor satellite arrays exhibited more extreme variation in copy number and CDI in comparison to the major satellite arrays (Fig.. - from the distinct biological functions of the major and minor satellite domains. - The minor satellite repeat binds to CENP-A, a specialized centromeric histone variant responsible for kinetochore complex specification and assembly [1]. - In- deed, at least in inbred strains, we show that shared evolu- tionary history is a poor predictor of minor satellite copy number and sequence heterogeneity, suggesting that minor satellite arrays evolve sufficiently rapidly to outstrip signals of recent shared descent. - Interestingly, ZALENDE/EiJ does not exhibit a par- allel decrease in the amount of major satellite DNA rela- tive to other inbred strains, indicating that the mechanism of Robertsonian fusion only leads to the loss of significant amounts of minor satellite DNA. - 6 Phylogenetic distribution of centromere satellite copy number and satellite heterogeneity in inbred strains and wild mice. - Indeed, the proportion of sequenced reads from this strain that map to the con- sensus minor satellite sequence is greater than expected based on the frequency of exact match k-mers (Supple- mentary Figure 5). - castaneus harbors the highest frequency of minor satellite k-mers, followed by M. - We observe only mod- est variation for both major and minor satellite k-mer frequencies between and within populations of wild- caught animals. - These values are notably higher for wild-caught mice (minor satellite. - At the very least, it is clear that there are striking chromosome-level differences in minor satellite array size among some inbred strains (Fig. - We also tested whether variation in minor satellite copy number leads to centromere drive in a mouse population developed from eight inbred strains with variable minor satellite copy numbers [48]. - We show that the major and minor satellite arrays in M. - For each pair of reads mapping to an identical site in the same orienta- tion on the major or minor satellite sequence, we com- puted the average number of observed sequence differences, d ij . - Major and minor satellite values were ana- lyzed independently. - frequencies were then converted to relative probabilities summing to one and used to populate a 4xN “polymorph- ism matrix” for each analyzed sample, where N = 120 for the minor satellite sequence and N = 234 for the major satellite. - musculus major and minor satellite sequences were PCR amplified and fluorescently labelled via nick trans- lation. - org/10.1186/s . - Principal compo- nent analysis of (A) major and (B) minor satellite consensus 31-mer frequencies in inbred strains and wild-caught M. - 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