rCRS vs. RSRS vs. HG19 (Yoruba)

It’s not always straight forward when working with the human mitochondrial DNA, even if it comes to the question: “what reference sequence do you use?” There should be just one reference and the questions therefore obsolete – what however is not the case.

Since the first sequencing of the human mitochondrial genome by Anderson et al. in 1981 the length was defined to be 16,569 base pairs naming it Cambridge Reference Sequence. Even if some years later errors in this first sequencing were corrected by Andrews et al. in 1999, (Genbank NC_012920.1) the new revised Cambridge Reference Sequence (rCRS) was kept the same length – although a deletion on 3107 was found, it was kept by introducing an N. So the 3107N is basically a deletion, kept so that the positions on CRS and rCRS are still comparable.
From many aspects, the choice of an european Haplogroup (H2a2a1) being the reference sequence is not the best one. Therefore Behar et al. proclaimed a new reference sequence in 2012 – a hypotetical one – the so called Reconstructed Sapiens Reference Sequence preserving the historical genome annotation numbering, but not starting with an leaf-sequence in the phylogenetic tree as is the case with the rCRS, but with a “mitochondrial Eve” as root. The two base insertion on 523-524 are represented as NN instead of AC, therefore the RSRS has 3 N positions (523N, 524N, 3107N). Mannis, the father of Phylotree made this table showing the differences between rCRS and RSRS.

We didn’t however change to the RSRS, since we agree with Bandelt et al., that an additional reference sequence causes confusion. But there’s yet another mtDNA reference sequence around, you should be aware of – present in GRCh37/ UCSC Hg19 or the older GRCh36/UCSC Hg18

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