8%). However, each PHP was unique in the dataset (observed in only a single individual). The absence of coding region PHPs detected in more than one individual is consistent with the recent analysis by Ramos et al. [54], which found 21 unique coding region PHPs among 101 individuals. Among SB431542 cost the 24 coding region PHPs reported by Li et al. [55], one was shared by more than one individual; however this PHP (3492M) is unlikely to be authentic in either individual, given (1) the very low incidence of transversion-type PHPs reported by Ramos et al. [54] and observed in this study (see below), (2)

the very low frequency of substitution at position 3492 (observed just once, and as a transition, among the more than 2000 mtGenomes learn more analyzed by Soares et al. [69]), (3) the identification (by the authors themselves) of position 3492 as a sequencing error hot spot, and (4) the coverage dip observed in this region in multiple mtGenome sequencing studies ([7], [18] and [70]; R. Just, unpublished data; and W. Parson, unpublished data) using Illumina platforms

(Illumina, Inc., San Diego, CA). In a slight departure from the absence of authentic shared PHPs in the datasets reported by Ramos et al. [54], Li et al. [55] and in this study, the haplotypes recently published by King et al. [7] included three shared PHPs (at positions 1438, 2083, and 8994) among the 58 total coding region PHPs detected (using an 18% threshold) in 283 individuals. When 203 coding

region PHPs (from the 1103 total mtGenomes published by Ramos et al. [54], Li et al. [55] (minus the 3492M PHPs), King et al. [7] and reported in this study) were considered in combination, only five additional PHPs were observed in more than one individual (see Table S10). All five of these positions had low relative substitution rates Rolziracetam (1–3) among the 2196 complete mtGenome sequences previously analyzed in a phylogenetic framework by Soares et al. [69]. In fact, of the 102 coding region PHPs in our data, only two occurred at positions among the 15 fastest evolving sites in the coding region (and only four among the 50 fastest sites), while nearly half (44%) occurred at positions invariant among the >2000 published mtGenomes included the Soares et al. analysis [69] (see Table S9). In combination, these studies suggest that the distribution of heteroplasmy (which should more closely reflect mutation rates than does complete substitution) in the coding region is not consistent with the gamma-distributed relative substitution rates reported for the region [69]. This finding is in contrast to the general correlation (with a few exceptions) between heteroplasmic hotspots and mutation/substitution hotspots in the CR [51].