Estimating metazoan divergence times with
a molecular clock
Kevin J. Peterson*, Jessica B. Lyons, Kristin S. Nowak, Carter M. Takacs, Matthew J. Wargo, and Mark A. McPeek

Department of Biological Sciences, Dartmouth College, Hanover, NH 03755

Communicated by Eric H. Davidson, California Institute of Technology, Pasadena, CA, March 18, 2004 (received for review December 1, 2003)

Accurately dating when the first bilaterally symmetrical animals
arose is crucial to our understanding of early animal evolution. The
earliest unequivocally bilaterian fossils are �555 million years old.
In contrast, molecular-clock analyses calibrated by using the fossil
record of vertebrates estimate that vertebrates split from dipterans
(Drosophila) �900 million years ago (Ma). Nonetheless, compara-
tive genomic analyses suggest that a significant rate difference
exists between vertebrates and dipterans, because the percentage
difference between the genomes of mosquito and fly is greater
than between fish and mouse, even though the vertebrate diver-
gence is almost twice that of the dipteran. Here we show that the
dipteran rate of molecular evolution is similar to other invertebrate
taxa (echinoderms and bivalve molluscs) but not to vertebrates,
which significantly decreased their rate of molecular evolution
with respect to invertebrates. Using a data set consisting of the
concatenation of seven different amino acid sequences from 23 in-
group taxa (giving a total of 11 different invertebrate calibration
points scattered throughout the bilaterian tree and across the
Phanerozoic), we estimate that the last common ancestor of
bilaterians arose somewhere between 573 and 656 Ma, depending
on the value assigned to the parameter scaling molecular substi-
tution rate heterogeneity. These results are in accord with the
known fossil record and support the view that the Cambrian
explosion reflects, in part, the diversification of bilaterian phyla.

Although the Cambrian explosion is of singular importance to our understanding of the history of life, it continues to defy
explanation (1). This defiance stems, in part, from our inability
to distinguish between two competing hypotheses: whether the
Cambrian explosion ref lects the rapid appearance of fossils with
animals having a deep but cryptic precambrian history, or
whether it ref lects the true sudden appearance and diversifica-
tion of animals in the Cambrian (2). Because each hypothesis
makes a specific prediction of when animals arose in time, one
way to distinguish between these two hypotheses is to date
animal diversifications by using a molecular clock (2). A number
of previous clock studies (reviewed in refs. 3 and 4) have
suggested that the last common ancestor of bilaterians (LCB)
lived well over one billion years ago (5, 6), whereas others suggest
that LCB arose �900 million years ago (Ma) (e.g.,

Mutation Pressure and the Evolution of Organelle Genomic Architecture

Author(s): Michael Lynch, Britt Koskella and Sarah Schaack

Source: Science , Mar. 24, 2006, New Series, Vol. 311, No. 5768, Climate Change: Breaking
the Ice (Mar. 24, 2006), pp. 1727-1730

Published by: American Association for the Advancement of Science

Stable URL: https://www.jstor.org/stable/3845710

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Mutation Pressure and the Evolution of

Organelle Genomic Architecture
Michael Lynch,t Britt Koskella,* Sarah Schaack*

The nuclear genomes of multicellular animals and plants contain large amounts of noncoding DNA,
the disadvantages of which can be too weak to be effectively countered by selection in lineages
with reduced effective population sizes. In contrast, the organelle genomes of these two lineages
evolved to opposite ends of the spectrum of genomic complexity, despite similar effective
population sizes. This pattern and other puzzling aspects of organelle evolution appear to be
consequences of differences in organelle mutation rates. These observations provide support for the
hypothesis that the fundamental features of genome evolution are largely defined by the relative
power of two nonadaptive forces: random genetic drift and mutation pressure.

The evolution of eukaryotes, and sub-
sequently of multicellularity, was ac-
companied by dramatic changes in the

nuclear genome, including expansions in sizes
and numbers of introns, proliferation of mobile
elements, and increases in lengths of intergenic
regions. The continuity in scaling of these
architectural features with genome size across
major phylogenetic groups suggests that cellular
and developmental features are not the primary
driving forces in genome evolution, and the
hypothesis ha

letters to nature

5. Charlesworth, B. The effect of background selection against deleterious mutations on weakly selected,
linked variants. Genet. Res. 63, 213±227 (1994).

6. Fay, J., Wycoff, G. J. & Wu, C.-I. Positive and negative selection on the human genome. Genetics 158,
1227±1234 (2001).

7. McDonald, J. H. & Kreitman, M. Adaptive evolution at the Adh locus in Drosophila. Nature 351, 652±
654 (1991).

8. Charlesworth, B., Morgan, M. T. & Charlesworth, D. The effect of deleterious mutations on neutral
molecular variation. Genetics 134, 1289±1303 (1993).

9. Maynard Smith, J. & Haigh, J. The hitch-hiking effect of a favourable gene. Genet. Res. 23, 23±35 (1974).
10. Begun, D. J. & Aquadro, C. F. levels of naturally occuring DNA polymorphism correlate with

recombination rates in D. melanogaster. Nature 356, 519±520 (1992).
11. Begun, D. The frequency distribution of nucleotide variation in Drosophila simulans. Mol. Biol. Evol.

18, 1343±1352 (2001).
12. Kliman, R. Recent selection on synonymous codon usage in Drosophila. J. Mol. Evol. 49, 343±351 (1999).
13. Adams, M. D. et al. The genome sequence of Drosophila melanogaster. Science 287, 2185±2195 (2000).
14. Powell, J. R. & DeSalle, R. Drosophila molecular phylogenies and their uses. Evol. Biol. 28, 87±138

15. Haldane, J. B. S. The cost of natural selection. J. Genet. 55, 511±524 (1957).
16. Kimura, M. Evolutionary rate at the molecular level. Nature 217, 624±626 (1968).
17. Thompson, J. D., Higgins, D. G. & Gibson, T. J. ClustalWÐimproving the sensitivity of progressive

multiple alignment through sequence weighting, position-speci®c gap penalties and weight matrix
choice. Nucl. Acids Res. 22, 4673±4680 (1994).

18. Xia, X. Data Analysis in Molecular Biology and Evolution (Kluwer Academic, London, 2000).
19. Rozas, J. & Rozas, R. DnaSP version 3: an integrated program for molecular population genetics and

molecular evolution analysis. Bioinformatics 15, 174±175 (1999).
20. Yang, Z. PAML: a program package for phylogenetic analysis by maximum likelihood. Comput. Appl.

Biosci. 13, 555±556 (1997).

Supplementary Information accompanies the paper on Nature’s website

We thank B. Charlesworth, C.-I. Wu, S. Otto, M. Whitlock, T. Johnson, P. Awadalla,
J. Gillespie, G. McVean and P. Keightley for helpful discussions, and E. Moriyama for help
with data collection. N.G.C.S. was funded by the Biotechnology and Biological Sciences
Research Council (BBSRC) and A.E.-W. is funded by the Royal Society and the BBSRC.

Competing interests statement
The authors declare that they have no competing ®nancial interests.

Correspondence and requests for materials should be addressed to A.E.-W.
(e-mail: a.c.eyre-walker@sussex.ac.uk).

Testing the neutral theory of
molecular evolution with
genomic data from Drosophila
Justin C. Fay*², Gerald J. Wycko


A Map of Recent Positive Selection
in the Human Genome

[ [ *
Benjamin F. Voight , Sridhar Kudaravalli , Xiaoquan Wen, Jonathan K. Pritchard

Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America

The identification of signals of very recent positive selection provides information about the adaptation of modern
humans to local conditions. We report here on a genome-wide scan for signals of very recent positive selection in favor
of variants that have not yet reached fixation. We describe a new analytical method for scanning single nucleotide
polymorphism (SNP) data for signals of recent selection, and apply this to data from the International HapMap Project.
In all three continental groups we find widespread signals of recent positive selection. Most signals are region-specific,
though a significant excess are shared across groups. Contrary to some earlier low resolution studies that suggested a
paucity of recent selection in sub-Saharan Africans, we find that by some measures our strongest signals of selection
are from the Yoruba population. Finally, since these signals indicate the existence of genetic variants that have
substantially different fitnesses, they must indicate loci that are the source of significant phenotypic variation. Though
the relevant phenotypes are generally not known, such loci should be of particular interest in mapping studies of
complex traits. For this purpose we have developed a set of SNPs that can be used to tag the strongest ;250 signals of
recent selection in each population.

Citation: Voight BF, Kudaravalli S, Wen X, Pritchard JK (2006) A map of recent positive selection in the human genome. PLoS Biol 4(3): e72.


The evolution of modern human populations has been
accompanied by dramatic changes in environment and
lifestyle. In the last 100,000 years, behaviorally modern
humans have spread from Africa to colonize most of the
globe. In that time, humans have been forced to adapt to a
wide range of new habitats and climates. Following the end of
the last ice age, 14,000 years ago, there was a major warming
event that raised global temperatures to roughly their current
levels. Further dramatic changes occurred with the transition
from hunter-gatherer to agricultural societies, starting about
10,000–12,000 years ago in the Fertile Crescent, and a little
later elsewhere. This was also a period marked by rapid
increases in human population densities. Increased popula-
tion density promoted the spread of infectious diseases, as
did the new proximity of farmers to animal pathogens [1,2].

Each of these kinds of changes likely resulted in powerful
selective pressures for new genotypes that were better suited
to the novel environments. Indeed, there are a number of
recent reports of genes that show signals of very strong and
recent selection in favor of new alleles: for example, in
response to malaria [3–5]; at

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