Hum Genet
DOI 10.1007/s00439-009-0747-1
RESPONSE
Response
Michael F. Hammer • Doron M. Behar • Tatiana M. Karafet
Fernando L. Mendez • Brian Hallmark • Tamar Erez •
Lev A. Zhivotovsky • Saharon Rosset • Karl Skorecki

Springer-Verlag 2009
We thank Dr. Klyosov for his Comment. The speed of
response is unusually impressive, and it covers a wide
scope. However, we are concerned that this haste may not
be in the best interest of the sound scientific process, as
evidenced by the heavy reliance on non-refereed publica-
tions, unpublished work and work not accessible to the
scientific reading audience through usual scientific
channels (categories that cover all five citations to
Dr. Klyosov’s previous work). Reference to non-peer
reviewed and poorly accessible data and formulations
renders the constructive critique process problematic.
Furthermore, the use of unconventional and ‘‘private’’
terms without definition or reference renders response
M. F. Hammer
T. M. Karafet
B. Hallmark
T. Erez
ARL Division of Biotechnology, University of Arizona,
Tucson, AZ 85721, USA
M. F. Hammer
F. L. Mendez
Department of EEB, University of Arizona, Tucson,
AZ 85721, USA
D. M. Behar
K. Skorecki
Molecular Medicine Laboratory, Rambam Health Care Campus,
31096 Haifa, Israel
L. A. Zhivotovsky
Institute of General Genetics, Russian Academy of Sciences,
119991 Moscow, Russia
S. Rosset
Department of Statistics and Operations Research,
School of Mathematical Sciences, Tel Aviv University,
69978 Tel Aviv, Israel
K. Skorecki (&)
Rappaport Faculty of Medicine and Research Institute,
Technion, Israel Institute of Technology, 31096 Haifa, Israel
e-mail: skorecki@tx.technion.ac.il
•
problematic. This includes terms such as ‘‘…genealogic
haplotype series’’. Moreover, a statement such as ‘‘Since
the logarithmic and linear methods give the same dating
the common ancestor, it means that there was indeed just
one common ancestor for the whole series of 98 of 22
marker haplotypes’’, lacks scientific rigor and robustness.
Nevertheless, we wish to provide some responses to the
best of our ability, given some of the limitations and
constraints noted above.
Before dealing with some of the specifics of the Com-
ment, we would like to address the issue of Y-STR muta-
tion rates and age estimates in general. Estimating times of
divergence and expansion requires knowledge regarding
the rate at which newly arisen genetic variation occurs and
is maintained in populations. Are these the usual mutation
rates that occur during meiosis or evolutionarily significant
substitution rates for randomly surviving mutations within
evolving haplogroups? Forster et al. (2000) and Heyer et al.
(2001) discovered up to a sevenfold difference between
‘‘familial’’ and ‘‘evolutionary’’ mutation rates (i.e., esti-
mated from pedigrees and phylogenetic trees, respectively)
for Y-chromosomal STRs and mtDNA. As discussed by
Zhivotovsky et al. (2004), there are several factors that may
underly this discrepancy. By examining Y-STR variation
within Y chromosome haplogroups (i.e., defined by unique
event polymorphisms) in populations with documented
short-term histories, they inferred an evolutionarily effec-
tive mutation rate of 0.00069 per 25 years on average,
which was threefold lower than previous estimates of the
familial mutation rate (Zhivotovsky et al. 2004). Together
with other methods, we used this approach in our paper
because it involved estimating the divergence time of Y
chromosome lineages with putative ages that were within a
similar time frame as those in the original Zhivotovsky
et al. (2004) study (i.e., the effective rate was calibrated for
123

time periods of *1,000 years). Since 2004, this approach
has been employed by other researchers and critically
evaluated in the scientific literature (e.g., Arredi et al.
2004; Di Giacomo et al. 2004; Gayden et al. 2007;
Sengupta et al. 2006; Xue et al. 2005; Zhivotovsky and
Underhill 2005). Subsequently, Zhivotovsky et al. (2006)
demonstrated that the evolutionarily effective mutation rate
strongly depends on population dynamics; in particular,
stochastic variation in the size of a SNP-lineage may lead
to the observed threefold difference. Therefore, under some
conditions estimating the time of ancient population events
represents a complex problem, depending upon unknown
ancient demographic parameters and uncertainty in muta-
tion rates. Given these challenges we tried to be clear about
the approaches that we used, and to avoid over-stating the
conclusions in our paper.
Dr. Klyosov’s Comment makes the erroneous claim that
the haplotypes found in a population (and representing a
sample) form a genealogy, and that ‘‘familial’’ rates are
therefore appropriate. For mutation rate estimates,
Dr. Klyosov (Comment, p. 13) refers to Chandler (2006);
however, this author suggests a method of estimating
relative mutation rates at Y-chromosomal STRs based on
haplotypic distributions in populations. For estimating
absolute mutation rates, Chandler (2006) used estimates of
overall Y-STR mutation rate from data on father-son pairs
obtained by Gusmão et al. (2005). Dr. Klyosov’s kinetics
equation (Comment, p. 12) operates on infinite-size popu-
lations and does not take into account the effects of genetic
drift, or any specific feature of microsatellite mutation. We
were not further informed on the relevance of this approach
when going through Dr. Klyosov’s self-cited previous
work, so far as we could gain access to it. Finally,
regarding the detailed ‘‘haplotype trees’’ offered by the
Comment, these are indeed interesting and can be very
instructive. However, it is critical to treat these trees with
great caution. We only observe extant samples, and
reconstruction is an algorithmic process subject to uncer-
tainty. Without a careful consideration and quantification
of this uncertainty, it is inappropriate to over-interpret such
trees.
References
Arredi B, Poloni ES, Paracchini S, Zerjal T, Fathallah DM, Makrelouf
M, Pascali VL, Novelletto A, Tyler-Smith C (2004) A
123
Hum Genet
predominantly neolithic origin for Y-chromosomal DNA varia-
tion in North Africa. Am J Hum Genet 75:338–345
Chandler JF (2006) Estimating per-locus mutation rates. J Genet
Geneal 2:27–33
Di Giacomo F, Luca F, Popa LO, Akar N, Anagnou N, Banyko J,
Brdicka R, Barbujani G, Papola F, Ciavarella G, Cucci F, Di
Stasi L, Gavrila L, Kerimova MG, Kovatchev D, Kozlov AI,
Loutradis A, Mandarino V, Mammi C, Michalodimitrakis EN,
Paoli G, Pappa KI, Pedicini G, Terrenato L, Tofanelli S,
Malaspina P, Novelletto A (2004) Y chromosomal haplogroup J
as a signature of the post-neolithic colonization of Europe. Hum
Genet 115:357–371
Forster P, Rohl A, Lunnemann P, Brinkmann C, Zerjal T, Tyler-Smith
C, Brinkmann B (2000) A short tandem repeat-based phylogeny
for the human Y chromosome. Am J Hum Genet 67:182–196
Gayden T, Cadenas AM, Regueiro M, Singh NB, Zhivotovsky LA,
Underhill PA, Cavalli-Sforza LL, Herrera RJ (2007) The
Himalayas as a directional barrier to gene flow. Am J Hum
Genet 80:884–894
Gusmão L, Sanchez-Diz P, Calafell F, Martin P, Alonso CA, Alvarez-
Fernandez F, Alves C, Borjas-Fajardo L, Bozzo WR, Bravo ML,
Builes JJ, Capilla J, Carvalho M, Castillo C, Catanesi CI, Corach
D, Di Lonardo AM, Espinheira R, Fagundes de Carvalho E,
Farfan MJ, Figueiredo HP, Gomes I, Lojo MM, Marino M,
Pinheiro MF, Pontes ML, Prieto V, Ramos-Luis E, Riancho JA,
Souza Goes AC, Santapa OA, Sumita DR, Vallejo G, Vidal
Rioja L, Vide MC, Vieira da Silva CI, Whittle MR, Zabala W,
Zarrabeitia MT, Alonso A, Carracedo A, Amorim A (2005)
Mutation rates at Y chromosome specific microsatellites. Hum
Mutat 26:520–528
Heyer E, Zietkiewicz E, Rochowski A, Yotova V, Puymirat J, Labuda
D (2001) Phylogenetic and familial estimates of mitochondrial
substitution rates: study of control region mutations in deep-
rooting pedigrees. Am J Hum Genet 69:1113–1126
Sengupta S, Zhivotovsky LA, King R, Mehdi SQ, Edmonds CA,
Chow CE, Lin AA, Mitra M, Sil SK, Ramesh A, Usha Rani MV,
Thakur CM, Cavalli-Sforza LL, Majumder PP, Underhill PA
(2006) Polarity and temporality of high-resolution Y-chromo-
some distributions in India identify both indigenous and
exogenous expansions and reveal minor genetic influence of
Central Asian pastoralists. Am J Hum Genet 78:202–221
Xue Y, Zerjal T, Bao W, Zhu S, Lim SK, Shu Q, Xu J, Du R, Fu S,
Li P, Yang H, Tyler-Smith C (2005) Recent spread of a
Y-chromosomal lineage in northern China and Mongolia. Am J
Hum Genet 77:1112–1116
Zhivotovsky LA, Underhill PA (2005) On the evolutionary mutation
rate at Y-chromosome STRs: comments on paper by Di Giacomo
et al. (2004). Hum Genet 116: 529–532
Zhivotovsky LA, Underhill PA, Cinnioglu C, Kayser M, Morar B,
Kivisild T, Scozzari R, Cruciani F, Destro-Bisol G, Spedini G,
Chambers GK, Herrera RJ, Yong KK, Gresham D, Tournev I,
Feldman MW, Kalaydjieva L (2004) The effective mutation rate
at Y chromosome short tandem repeats, with application to
human population-divergence time. Am J Hum Genet 74:50–61
Zhivotovsky LA, Underhill PA, Feldman MW (2006) Difference
between evolutionarily effective and germ line mutation rate due
to stochastically varying haplogroup size. Mol Biol Evol
23:2268–2270