True Age of mt-Eve based on Direct Pedigree Method

Since no one had took effort to calculate the true age of mtEve based on directly observed pedigree method (as I can’t find any paper), I am taking that effort now to post it as a blog.

… Keep on seeing, but do not perceive.

Isa 6:9

HVR1 Estimation

Based on a recently published paper1, I thought of estimating the age of mt-Eve. The paper is the result of the analysis of HVR1 on 19 deep-rooted pedigree in a population of mixed origin in Costa Rica.

As you can see, there are at-least 7 mutations in 289 transmissions. Which means, there is a probability of (7/289) 0.024221 for every transmission to have a mutation. In other worlds, 1 new mutation can occur every 41 generations.

Now, let us consider how much mutations we have from mtEve. To look into it, let me consider the number of mutations from several FTDNA projects to find the maximum and minimum genetic distance. Kit #50252 from Cumberlandgap-mtdna project2 as 14 mutations while Kit #258240 has only 3 mutations, from X mtDNA project3. As you can see, the HVR1 mutations vary from 3 to 14 as distance from RSRS (or mtEve). There could be even more extremes but, let’s consider an average 8.5 mutations from mtEve for HVR1. This is reasonable because, if you take any mtDNA project from FTDNA, you will notice atleast on average 8 mutations in HVR1 for RSRS.

One mutation can occur every 41 generations and humans have 8.5 mutations on average as genetic distance from mtEve. So, there should be 41 x 8.5 generations from mtEve. If we consider 20 years for 1 generation, we have 41 x 8.5 x 20 = 6970 years as the age for mtEve.

The age of mtEve using HVR1 alone gives 6970 years.

HVR1 & HVR2 Estimation – Parsons Paper

In the paper, A high observed substitution rate in the human mitocondrial DNA control region4, which includes HVR1 and HVR2, they took samples from Armed Forced DNA Identification Laboratory, Oxford British families, CEPH pedigree cell lines and Old Order Amish pedigree cell lines.

They found 10 mutations in 327 generational events. Which means, there is a probability of (10/327) 0.03058 for every transmission to have a mutation. In other worlds, 1 new mutation can occur every 33 generations.

Now, let us consider how much mutations we have from mtEve. To look into it, let me consider the number of mutations from several FTDNA projects to find the maximum and minimum genetic distance. Based on kits #282059 and #50252 from Cumberlandgap-mtdna project2, the maximum mutations for HVR1 and HVR2 from RSRS is 22. Based on kits #N48849 and #N23635 from X mtDNA project3, the minimum mutations from RSRS is 10. As you can see, the HVR1 and HVR2 mutations vary from 10 to 22 as distance from RSRS (or mtEve). So, let’s consider an average 16 mutations from mtEve for HVR1 and HVR2. This is reasonable because, if you take any mtDNA project from FTDNA, you will notice atleast on average 16 mutations in HVR1 and HVR2 for RSRS.

One mutation can occur every 33 generations and humans have 16 mutations on average as genetic distance from mtEve. So, there should be 33 x 16 generations from mtEve. If we consider 20 years for 1 generation, we have 33 x 16 x 20 = 10560 years as the age for mtEve.

The age of mtEve using HVR1 and HVR2 gives 10560 years.

HVR1 and HVR2 Estimation – Santos Paper

In the paper, Understanding Differences Between Phylogenetic and Pedigree-Derived mtDNA Mutation Rate: A Model Using Families from the Azores Islands (Portugal)5, based on 321 mtDNA transmissions they detected 11 substitutions in the D-loop (more precisely, in 973 bp located between positions 16024–16596 of HVR1 and 1–400 of HVR2), which implies that 0.0343 mutations occur (at a detectable level) in the D-loop in each generation (95% CI: 0.014–0.054). The paper then adds, if we employ the same deﬁnition of mutation used by other authors (for example Howell et al. 2003), only mutations for which there is evidence that they are germinal should be considered (see table 2). This implies that the mutation rate would be reduced almost by half: six mutations in 321 mtDNA transmissions, that is, 0.0187 mutations/generation for the entire D-loop.

In other words, 1 mutation can occur every 53.5 generations. With humans having 16 mutations from RSRS for HVR1 and HVR2, mtEve should be 53.5 x 16 generations. If we consider 20 years for 1 generation, we have 53.5 x 16 x 20 = 17120 years as the age for mtEve.

The age of mtEve using HVR1 and HVR2 gives 17120 years.

HVR1 and HVR2 Estimation – Other Papers

Some of the other papers that agree with the above two results include the following:

Hence, based on HVR1 and HVR2, the age of mtEve should be approximately within a range of 9000 to 17000 ybp.

HVR1, HVR2 and Coding Region Estimation

Based on the paper, The pedigree rate of sequence divergence in the human mitochondrial genome: There is a difference between phylogenetic and pedigree rates6,

The cumulative coding region data presented here can be combined with those published elsewhere (Howell et al. 1996), to derive a preliminary estimate of the pedigree divergence rate. Excluding the LHON mutations, the rate of newly arising germline mutations in the coding region is as follows: TAS1, 0 mutations/107 transmission events; ENG1, 1 mutation/26 transmission events; USA1, 1 mutation/11 transmission events; NWC1, 1 mutation/9 transmission events; and QLD1, 1 mutation/17 transmission events. Thus, there are 4 coding region mutations/170 transmission events, or ∼0.15 mutations/bp/Myr (99.5% CI 0.02–0.49).

Thus 4 coding region mutations for 170 transmissions. In other words, 4/170 = 0.02353 mutations per generation. For HVR1 and HVR2, we have 10/327 = 0.03058 mutations per generation (based on Parsons Paper). Since these two events are not mutually exclusive and the formula is P(A or B) = P(A) + P(B) – P(A and B).

P(Any mutation HVR1,HVR2 or CR) = 4/170 + 10/327 – (4/170 x 10/327) = 0.05339 (or 1 mutation every ~18 generations). With 57 mutations from mtEve, and 1 mutation takes 18 generations, mtEve must be 1026 generations back. Considering 20 years for 1 generation, mtEve must be 1026 x 20 = 20520 ybp.

Considering Santos Paper, having a mutation rate of 6/321 per generation, and combining with coding region mutation rate, we get, P(Any mutation HVR1,HVR2 or CR) = 4/170 + 6/321 – (4/170 x 6/321) = 0.04178 (or 1 mutation every ~24 generations). With 57 mutations from mtEve, and considering 20 years for 1 generation, mtEve must be 24 x 57 x 20 = 27360 ybp.

Hence, mtEve based overall mtDNA mutations including HVR1, HVR2 and Coding Region, gives a range of 20520 to 27360 years before present.

Conclusion

• HVR1 alone provides an age estimation of 6970 ybp.
• HVR1 and HVR2 provides an age estimation of 9000 to 17000 ybp.
• HVR1, HVR2 and Coding Region provides an age estimation of 20520 to 27360 ybp.

Since some mutations on coding region can be lethal, estimation based on coding region can be inaccurate and too exaggerated because, the harmful mutations might be missing as they would have made the mutated person dead and thus the lineage is lost and the number of observed mutations become less. Hence, the overall estimation should be taken with a grain of salt must be taken well below the lower end for calculation that includes coding region.

Many scientists do acknowledge that the direct verifiable pedigrees mtDNA mutation rates are observed to be much higher in the order of 10x times compared to the phylogenetic mutation rates which are non-observable and has several assumptions.

The real value of mutation rate in humans has recently been the subject of an intense debate between those advocating the use of a phylogenetic mutation rate (~3 x 10^-6 substitutions per site per generation of 20 yr) calibrated by the divergence between humans and chimpanzees (Jazin et al. 1998) and those studying the mutation process directly on pedigrees giving numbers ~10 times larger (~2.7-3 10^-5 substitutions per site per generation; Howell et al. 1996; Parsons et al. 1997; Parsons and Holland 1998).7

Hence, the true mtEve age should be between 6000 – 25000 ybp based on directly observed pedigree method.

1 High mitochondrial mutation rates estimated from deep‐rooting costa rican pedigrees – Madrigal – 2012 – American Journal of Physical Anthropology – Wiley Online Library. Retrieved December 30, 2020, from https://onlinelibrary.wiley.com/doi/abs/10.1002/ajpa.22052

2 FamilyTreeDNA – Cumberland Gap Mitochondrial DNA (mtdna). Retrieved December 30, 2020, from https://www.familytreedna.com/public/Cumberlandgap-mtdna/default.aspx?section=mtresults

3 FamilyTreeDNA – X mtDNA Haplogroup. Retrieved December 30, 2020, from https://www.familytreedna.com/public/x/default.aspx?section=mtresults

4 Substitutions At Mutational. (2020) A high observed substitution rate in the human mitochondrial DNA control region – PubMed. Retrieved December 30, 2020, from https://pubmed.ncbi.nlm.nih.gov/9090380/

5 Which A New. (2020) Understanding differences between phylogenetic and pedigree-derived mtDNA mutation rate: a model using families from the Azores Islands (Portugal) – PubMed. Retrieved December 30, 2020, from https://pubmed.ncbi.nlm.nih.gov/15814829/

6 Bandelt Et Al. (2020) The Pedigree Rate of Sequence Divergence in the Human Mitochondrial Genome: There Is a Difference Between Phylogenetic and Pedigree Rates – ScienceDirect. Retrieved December 30, 2020, from https://www.sciencedirect.com/science/article/pii/S0002929707605813

7 Explicitly Taking Into. (2020) Estimation of past demographic parameters from the distribution of pairwise differences when the mutation rates vary among sites: application to human mitochondrial DNA – PubMed. Retrieved December 30, 2020, from https://pubmed.ncbi.nlm.nih.gov/10388826/

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