Spotlight

A showcase of research and scholarship

in selected articles from 2016
2016/17
Editorial Board CELLULAR GENETICS Krista M. Nichols William T. Sullivan
Bruce Beutler NOAA Fisheries University of California,
Mark Johnston,
The University of Texas Santa Cruz
Editor-in-Chief Andrew H. Paterson
University of Colorado Southwestern Medical University of Georgia Meera V. Sundaram
School of Medicine Center University of
Katie Peichel
Sue Biggins Pennsylvania
Tracey DePellegrin Fred Hutchinson
Executive Editor Fred Hutchinson Cancer Research Mariana F. Wolfner
Cancer Research Center Cornell University
Ruth Isaacson Center
Managing Editor Paul Scheet
Orna Cohen-Fix MD Anderson Cancer
NIDDK, National GENE EXPRESSION
Center
SENIOR EDITORS Institutes of Health James A. Birchler
David W. Threadgill University of Missouri
Karen M. Arndt Amy S. Gladfelter Texas A&M University
University of University of North Michael Freitag
Pittsburgh Carolina at Chapel Hill Fred van Eeuwijk Oregon State University
& Dartmouth College Wageningen University
Nick H. Barton Pamela Geyer
Institute of Science Bob Goldstein Jason B. Wolf University of Iowa
and Technology University of North University of Bath
Michael Hampsey
Austria Carolina at Chapel Hill Naomi R. Wray Rutgers Robert Wood
Karl Broman Joseph Heitman The University of Johnson Medical
University of Duke University Queensland School
Wisconsin-Madison Medical Center Alan G. Hinnebusch
Gary A. Churchill Daniel J. Lew DEVELOPMENTAL NICHD, National
The Jackson Duke University AND BEHAVIORAL Institutes of Health
Laboratory Medical Center GENETICS
Craig Kaplan
Stanley Fields Piali Sengupta Hugo J. Bellen Texas A&M University
University of Brandeis University Baylor College of
Medicine Mitzi Kuroda
Washington Harvard Medical School
Yongbiao Xue
Audrey Gasch Chinese Academy of Giovanni Bosco
Geisel School of Aaron P. Mitchell
University of Sciences Carnegie Mellon
Wisconsin-Madison Medicine at Dartmouth
University
David I. Greenstein Kym M. Boycott
COMPLEX TRAITS CHEO Research Oliver J. Rando
University of Minnesota University of
Joshua M. Akey Institute
Oliver Hobert University of Massachusetts
Columbia University Lynn Cooley Medical School
Washington
Yale University
Terry R. Magnuson Alain Charcosset Nathan Springer
University of North Robert J. Duronio University of Minnesota
Institut National
Carolina at Chapel Hill University of North
de la Recherche Elizabeth Tran
Carolina at Chapel Hill
Michael W. Nachman Agronomique Purdue University
University of California, Marnie E. Halpern
Stephen Chenoweth
Berkeley Carnegie Institution for
The University of
Science GENOME INTEGRITY
Mark D. Rose Queensland
AND TRANSMISSION
Princeton University Iswar K. Hariharan
Elizabeth Hauser Anne Britt
University of California,
Jeff Sekelsky Duke University UC Davis
Berkeley
University of North Dirk Jan de Koning Brian R. Calvi
Carolina at Chapel Hill Abraham A. Palmer
Swedish University of Indiana University
University of Chicago
John C. Schimenti Agricultural Sciences
David M. Parichy Monica P. Colaicovo
Cornell University Corbin D. Jones Harvard Medical School
University of
John Wakeley University of North
Washington Andreas Houben
Harvard University Carolina at Chapel Hill
R. Scott Poethig Leibniz Institute of
Thomas E. Juenger Plant Genetics and
University of
University of Texas Crop Plant Research
Pennsylvania
Loeske E. B. Kruuk Neil Hunter
Trudi Schpbach
University of Edinburgh University of California,
Princeton University
Davis
James R. Lupski Jay Shendure Joachim Hermisson
STATISTICAL
Baylor College of University of University of Vienna
GENETICS AND
Medicine GENOMICS Washington
Joanna Masel
Jac A. Nickoloff Mario Calus David W. Threadgill University of Arizona
Colorado State Wageningen UR Texas A&M University
Rasmus Nielsen
University Livestock Research
University of
Steven J. Sandler Eleazar Eskin EMPIRICAL
California, Berkeley
University of University of California, POPULATION and University of
Massachusetts Los Angeles GENETICS Copenhagen
Shyam K. Sharan Ina Hoeschele Daniel A. Barbash Sohini Ramachandran
NCI, National Institutes Virginia Polytechnic Cornell University Brown University
of Health Institute and State David J. Begun Noah A. Rosenberg
University University of California,
Jennifer Surtees Stanford University
University at Buffalo Christina Kendziorski Davis
Yun S. Song
University of Deborah Charlesworth University of California,
Wisconsin-Madison University of Edinburgh
GENOME AND Berkeley
SYSTEMS BIOLOGY Neil Risch Santiago C. Gonzlez- Tanja Stadler
University of California, Martnez
Kirsten Bomblies ETH Zrich
San Francisco Forest Research
John Innes Centre
Centre (CIFOR-INIA) Wolfgang Stephan
Chiara Sabatti
Charles Boone University of Munich
Stanford University Matthew W. Hahn
University of Toronto
Indiana University Lindi M. Wahl
Saunak Sen
Brian P. Lazzaro Western University
University of Tennessee Lynn B. Jorde
Cornell University
Health Science Center University of Utah Jeff D. Wall
Jeffery F. Miller University of California,
Mikko J. Sillanp Charles H. Langley
University of California, San Francisco
University of Oulu University of California,
Los Angeles
Eric A. Stone Davis
Alan Moses PRIMERS
North Carolina State Jeffrey G. Lawrence
University of Toronto
University University of Pittsburgh Elizabeth A. De Stasio
Andrew W. Murray Lawrence University
William Valdar Brian P. Lazzaro
Harvard University
University of North Cornell University
Norbert Perrimon Carolina at Chapel Hill
PERSPECTIVES
Harvard Medical School Leonie C. Moyle
Nengjun Yi Indiana University H. Allen Orr
Enrico G. Petretto University of Alabama University of Rochester
Duke-NUS Graduate at Birmingham John Novembre
Medical School University of Chicago Adam S. Wilkins
Singapore Humboldt University
Bret A. Payseur of Berlin
METHODS,
Valerie Reinke University of
TECHNOLOGY, AND
Yale University RESOURCES Wisconsin-Madison
Charles Boone Daven Presgraves REVIEWS
Jay Shendure
University of University of Toronto University of Rochester Oliver Hobert
Washington Columbia University
Hannes Blow Daniel M. Weinreich
Lars M. Steinmetz Albert Einstein College Brown University Jasper Rine
European Molecular of Medicine University of California,
Stephen I. Wright
Biology Laboratory & Berkeley
George M. Church University of Toronto
Stanford University Michael Turelli
Harvard Medical School
David Valle University of California,
Liqun Luo THEORETICAL Davis
Johns Hopkins
Stanford University POPULATION
University School of Jeffrey H. Miller
Norbert Perrimon GENETICS
Medicine University of California,
Harvard Medical School Mark A. Beaumont
Los Angeles
University of Bristol
Jeff Sekelsky
University of North Graham Coop
Carolina at Chapel Hill University of California, SERIES
Davis Lauren M. McIntyre
University of Florida
IN THEIR OWN WORDS

I had a very positive experience submitting our paper to

GENETICS. The reviewers were fair and asked good questions;
the editor was very efficient and gave us good instruction on
how to best address them. I am quite happy to see how the
paper was improved by the review process.
Rebecca Yang
Yale University

In my dealings with several different editors at a number of

journals my experience at GENETICS has been really great. I
think that David Greenstein was simply exceptional and by
far the best editor I have ever worked with. His combination
of reasonable patience, his insight and his willingness to work
with scientists to get the best out of their data was incomparable
and has convinced me that I will be sending more manuscripts
to your journal. It is finally a place where science counts but
where scientists and their diverse situations are also considered.
Kudos and keep up the good work.
Richard Roy
McGill University

I enjoyed the review process and learned a lot from it.

Very important as a new PI!
Michael Downey
University of Ottawa

Indeed, it is the best work of our group that we reserve for

submission to GENETICS because this is undoubtedly
the leading journal in our field. The tremendous influence of
articles published in GENETICS is nicely illustrated by the series
of classic papers celebrating the 100th anniversary of this journal.
Albrecht E. Melchinger
University of Hohenheim

ON THE COVER Przewalskis horses reintroduced at Seer, Mongolia by the Association

Takh pour le cheval de Przewalski. Librado et al. reviewed the genetic changes that
led from wild horses living on the Eurasian steppes 5,500 years ago to the many highly
specialized breeds of domestic horse that exist today. Genetics 204: 423-424
2 Photo: Ludovic Orlando.
This spotlight showcases a diverse sampling of the
research published in GENETICS in 2016the journals
Centennial year. In the broad range of work weve
featured, youll see that 100 years after its founding
GENETICS continues to publish some of the best and
most important work in the field.

The breadth of our journal is part of its strength.

Alongside leading work in theoretical and empirical
population genetics, you can read about outstanding
molecular genetics research. Quantitative and applied
genetics are well represented, as also reflected in the
success of our Genomic Selection and Multiparental
Populations series. The Methods, Technology, and
Resources section includes useful methods like the
rapid sequencing approach highlighted in this Spotlight.
Because new technologies empower geneticists to
address previously unapproachable questions, we are
especially keen to receive submissions of manuscripts
to this section.

This year we have again highlighted especially significant

papers with our Editors Choice awards. As usual,
there were many papers worthy of recognition, so our
choices were difficult (a problem we are glad to have).
After much deliberation we settled on three outstanding
examples of the best GENETICS had to offer in 2016.

This Spotlight offers only a glimpse of GENETICS

Centennial year. I urge you to visit www.genetics.org
to check out the special articles we commissioned
to celebrate the journals first century and to look to
the fields second century. I hope our long history and
recent innovation will encourage you to submit your
best work for publication in GENETICS, a peer-edited
journal of the Genetics Society of America.

Mark Johnston
Editor-in-Chief, GENETICS 3
 2016 EDITORS CHOICE AWARD: MOLECUL AR GENE TICS

Degradation of the Mitotic Cyclin Clb3 Is not

Required for Mitotic Exit but Is Necessary for
G1Cyclin Control of the Succeeding Cell Cycle
Kresti Pecani and Frederick R. Cross
Genetics December 2016 204:14791494

EDITORS NOTE In the textbook picture of cell cycle function, B-type cyclins
must be degraded to allow the cell to exit mitosis. Pecani et al. show that
blocking degradation of yeast B-type cyclin Clb3 by removal of its destruction
signal does not prevent mitotic exit. Instead, the cyclins persistence in new cells
bypasses normal controls governing the start of the next cycle, including by cell
size, pheromones, and G1 cyclins. The discovery that Clb3 destruction is not
needed for mitotic exit has revealed a previously obscure role for mitotic cyclin
degradation: blocking memory of the preceding cell cycle in newborn cells.

ABSTRACT B-type cyclins promote mitotic entry and inhibit mitotic exit. In
Saccharomyces cerevisiae, four B-type cyclins, Clb14, carry out essential
mitotic roles, with substantial but incomplete overlap of function among them.
Previous work in many organisms has indicated that B-type cyclin-dependent
inhibition of mitotic exit imposes a requirement for mitotic destruction of
B-type cyclins. For instance, precise genomic removal of the Clb2 destruction
box (D box) prevents mitotic proteolysis of Clb2, and blocks mitotic exit. Here,
we show that, despite significant functional overlap between Clb2 and Clb3,
D-box-dependent Clb3 proteolysis is completely dispensable for mitotic exit.
Removal of the Clb3 D box results in abundant Clb3 protein and associated
kinase throughout the cell cycle, but mitotic exit occurs with close to normal
timing. Clb3 degradation is required for pre-Start G1 control in the succeeding
cell cycle. Deleting the CLB3 D box essentially eliminates all time delay
before cell cycle Start following division, even in very small newborn cells.
CLB3db cells show no cell cycle arrest response to mating pheromone, and
CLB3db completely bypasses the requirement for CLN G1 cyclins, even in
the absence of the early expressed B-type cyclins CLB5,6. Thus, regulated
mitotic proteolysis of Clb3 is specifically required to make passage of Start
in the succeeding cell cycle memorylessdependent on conditions within
that cycle, and independent of events such as B-type cyclin accumulation that
occurred in the preceding cycle.

4
 2016 EDITORS CHOICE AWARD: POPUL ATION GENE TICS

The Genetic Cost of Neanderthal

Introgression
Kelley Harris and Rasmus Nielsen
Genetics June 2016 203: 881-891

EDITORS NOTE Compared to humans, Neanderthals were inbred. Harris

and Nielsen use simulations to show that this inbreeding likely caused the
accumulation of harmful mutations. They estimate that inbreeding may have
led to Neanderthals having 40% lower fitness than humans. Some of these
harmful mutations are predicted to persist in modern populations, although
most have been eliminated by natural selection in humans since the time of
interbreeding.

ABSTRACT Approximately 24% of genetic material in human populations

outside Africa is derived from Neanderthals who interbred with anatomically
modern humans. Recent studies have shown that this Neanderthal DNA
is depleted around functional genomic regions; this has been suggested
to be a consequence of harmful epistatic interactions between human and
Neanderthal alleles. However, using published estimates of Neanderthal
inbreeding and the distribution of mutational fitness effects, we infer that
Neanderthals had at least 40% lower fitness than humans on average; this
increased load predicts the reduction in Neanderthal introgression around
genes without the need to invoke epistasis. We also predict a residual
Neanderthal mutational load in non-Africans, leading to a fitness reduction
of at least 0.5%. This effect of Neanderthal admixture has been left out of
previous debate on mutation load differences between Africans and non-
Africans. We also show that if many deleterious mutations are recessive, the
Neanderthal admixture fraction could increase over time due to the protective
effect of Neanderthal haplotypes against deleterious alleles that arose recently
in the human population. This might partially explain why so many organisms
retain gene flow from other species and appear to derive adaptive benefits
from introgression.

5
 2016 EDITORS CHOICE AWARD: QUANTITATIVE GENE TICS

Evolution of Schooling Behavior in Threespine

Sticklebacks Is Shaped by the Eda Gene
Anna K. Greenwood, Margaret G. Mills, Abigail R. Wark, Sophie L. Archambeault, and
Catherine L. Peichel
Genetics June 2016 203: 677681

EDITORS NOTE Genes are known to play an important role in behavior, but
there are few cases in which variation in a specific gene has been linked to a
natural, ecologically relevant behaviorparticularly in vertebrates. Greenwood
et al. find that natural variation in schooling behavior between two populations
of threespine sticklebacks is caused by the pleiotropic gene Ectodysplasin,
which is also known to affect the development of body armor and the
sensory organs that fish use to detect water movement. This is one of the
first examples of a genetic change that underlies the evolution of vertebrate
behavior in the wild.

ABSTRACT Despite longstanding interest in the genetic mechanisms that

underlie behavioral evolution, very few genes that underlie naturally occurring
variation in behavior between individuals or species are known, particularly
in vertebrates. Here, we build on our previous forward genetic mapping
experiments and use transgenic approaches to identify Ectodysplasin as a
gene that causes differences in schooling behavior between wild populations
of threespine stickleback (Gasterosteus aculeatus) fish. This work provides
rare insight into the proximate mechanisms that have shaped the evolution of
vertebrate behavior.

6
BACK TO SCHOOL To measure schooling behaviors, a stickleback
is placed in a tank with several model fish. When the models begin
to move, the real fish attempts to school with them. This allows the
researchers to quantify both the sticklebacks willingness to school and
its ability to maintain a body position parallel to the models, which is a
proxy for its schooling skill. Photo: Anna Greenwood.

7
 GENE TICS CENTENNIAL

To celebrate 100 years since the founding of GENETICS, the Centennial series
looked back at our remarkable pastand forward to the next century of the field.
With fifty articles published, here is just a small sampling of this popular series.

Classics: Introductions to 25 Classic GENETICS papers

Sydney Brenner on the Genetics of Caenorhabditis elegans
Bob Goldstein
Genetics September 2016 204: 12
Barbara McClintock on Defining the Unstable Genome
Marnie E. Halpern
Genetics September 2016 204: 34

Commentary: Brief reflections on the future of Genetics

Genetic Time Travel
Johannes Krause and Svante Pbo
Genetics May 2016 203: 912
Probing the Depths of Biological Diversity During the Second Century of GENETICS
Linnea Sandell and Sarah P. Otto
Genetics October 2016 204: 395400

Perspectives: In-depth analysis of the history of genetics

The Centenary of GENETICS: Bridges to the Future
Barry Ganetzky and R. Scott Hawley
Genetics January 2016 202: 1523

Primers: Educational resources

Pick Your Poisson: An Educational Primer for Luria and Delbrcks Classic Paper
Philip M. Meneely
Genetics February 2016 202: 371375

8
 EVOLVING GENETICS In the centennial year of GENETICS, Telis et al.
characterized changes in the focus of genetic research by studying abstracts and
titles of articles published since 1916 in GENETICS. They describe increasingly
global publishing, with a corresponding increase in the number of authors on
papers. They document the turnover of techniques and concepts, increasing in pace
after the major breakthroughs of the 1950s. They also record dramatic increases and
declines in the popularity of some organism models, though others stay constant
through the century. (A) Proportions of all papers that contain at least a single
reference to a particular category of organism. (B) A semilog plot of proportions
of all papers published in a decade that mention a particular organism.

A Bibliometric History of the Journal GENETICS

Natalie Telis, Benjamin V. Lehmann, Marcus W. Feldman, and
Jonathan K. Pritchard
Genetics December 2016 204: 13371342 9
 CELLUL AR GENE TICS

Maternal MEMI Promotes Female Meiosis II

in Response to Fertilization in
Caenorhabditis elegans
Maryam Ataeian, Justus Tegha-Dunghu, Donna G. Curtis, Ellen M. E. Sykes, Ashkan
Nozohourmehrabad, Megha Bajaj, Karen Cheung, and Martin Srayko
Genetics December 2016 204: 14611477

Commentary:
Parental Control Begins at the Beginning
Diana Chu
Genetics December 2016 204: 13771378

EDITORS NOTE In most animals, female meiosis completes only after

fertilization. In C. elegans, fertilization is required to initiate female meiosis II,
but it is unclear how the oocyte senses sperm entry. Ataeian et al. identify
an oocyte-specific factor required for the female meiosis II program. Using a
sensitive genetic screen, they also identify a sperm-specific phosphatase that
could be part of the elusive signal that triggers meiosis II.

ABSTRACT In most animals, female meiosis completes only after fertilization.

Sperm entry has been implicated in providing a signal for the initiation of the
final meiotic processes; however, a maternal component required for this
process has not been previously identified. We report the characterization of
a novel family of three highly similar paralogs (memi-1, memi-2, memi-3) that
encode oocyte-specific proteins. A hypermorphic mutation memi-1(sb41)
results in failure to exit female meiosis II properly; however, loss of all three
paralogs results in a skipped meiosis II phenotype. Mutations that prevent
fertilization, such as fer-1(hc1), also cause a skipped meiosis II phenotype,
suggesting that the MEMI proteins represent a maternal component of a
postfertilization signal that specifies the meiosis II program. MEMI proteins are
degraded before mitosis and sensitive to ZYG-11, a substrate-specific adapter
for cullin-based ubiquitin ligase activity, and the memi-1(sb41) mutation results
in inappropriate persistence of the MEMI-1 protein into mitosis. Using an RNAi
screen for suppressors of memi-1(sb41), we identified a sperm-specific PP1
phosphatase, GSP-3/4, as a putative sperm component of the MEMI pathway.
We also found that MEMI and GSP-3/4 proteins can physically interact via
co-immunoprecipitation. These results suggest that sperm-specific PP1 and
maternal MEMI proteins act in the same pathway after fertilization to facilitate
proper meiosis II and the transition into embryonic mitosis.

10
ORIGINS In 1916, in the first issue of GENETICS, Calvin Bridges published his
proof that genes are carried on chromosomes. The Centennial cover illustration
was created by Alex Cagan (Max Planck Institute for Evolutionary Anthropology),
featuring karyotypes and diagrams from Bridges original paper. Cagan says he
wanted to capture the sense of excitement and discovery Bridges must have felt
while pioneering the use of Drosophila in genetics. He also describes the karyotypes
as a natural form of calligraphy.

11
 DE VELOPMENTAL & BEHAVIOR AL GENE TICS

Hedgehog Signaling Strength Is Orchestrated

by the mir-310 Cluster of MicroRNAs in
Response to Diet
Ibrahim mer iek, Samir Karaca, Marko Brankatschk, Suzanne Eaton, Henning
Urlaub, and Halyna R. Shcherbata
Genetics March 2016 202:11671183

EDITORS NOTE iek et al. show that nutritional status in Drosophila is

perceived and interpreted via miRNAs. To ensure a fast and robust dietary
response, the mir-310s target multiple genes associated with Hedgehog (Hh)
signaling. One of these targets, Rab23, is a novel component of Drosophila Hh
signaling that regulates Hh ligand trafficking in the stem cell niche in response to
diet. They propose that targeting of several components of the same pathway is
a crucial principle of miRNA-based regulation in unfavorable conditions.

ABSTRACT Since the discovery of microRNAs (miRNAs) only two decades

ago, they have emerged as an essential component of the gene regulatory
machinery. miRNAs have seemingly paradoxical features: a single miRNA is
able to simultaneously target hundreds of genes, while its presence is mostly
dispensable for animal viability under normal conditions. It is known that
miRNAs act as stress response factors; however, it remains challenging to
determine their relevant targets and the conditions under which they function.
To address this challenge, we propose a new workflow for miRNA function
analysis, by which we found that the evolutionarily young miRNA family,
the mir-310s (mir-310/mir-311/mir-312/mir-313), are important regulators of
Drosophila metabolic status. mir-310s-deficient animals have an abnormal
diet-dependent expression profile for numerous diet-sensitive components,
accumulate fats, and show various physiological defects. We found that the
mir-310s simultaneously repress the production of several regulatory factors
(Rab23, DHR96, and Ttk) of the evolutionarily conserved Hedgehog (Hh)
pathway to sharpen dietary response. As the mir-310s expression is highly
dynamic and nutrition sensitive, this signal relay model helps to explain the
molecular mechanism governing quick and robust Hh signaling responses
to nutritional changes. Additionally, we discovered a new component of
the Hh signaling pathway in Drosophila, Rab23, which cell autonomously
regulates Hh ligand trafficking in the germline stem cell niche. How organisms
adjust to dietary fluctuations to sustain healthy homeostasis is an intriguing
research topic. These data are the first to report that miRNAs can act as
executives that transduce nutritional signals to an essential signaling pathway.
This suggests miRNAs as plausible therapeutic agents that can be used
in combination with low calorie and cholesterol diets to manage quick and
precise tissue-specific responses to nutritional changes.

12
 GENE E XPRESSION

Multitasking of the piRNA Silencing

Machinery: Targeting Transposable Elements
and Foreign Genes in the Bdelloid Rotifer
Adineta vaga
Fernando Rodriguez and Irina R. Arkhipova
Genetics May 2016 203:255268

EDITORS NOTE The genome of the bdelloid rotifer Adineta vaga is

characterized by massive horizontal gene transfer, low transposon content,
and highly diversified RNA-mediated silencing machinery. The authors
investigated genome-wide distribution of A. vaga piRNAs and found that
an unexpectedly large fraction matches foreign genes. Small-RNA covered
genes have a higher frequency of nearby telomeric repeats and transposons,
indicating that gene acquisition occurs largely at the genome periphery,
where it can be affected by RNA-based silencing.

ABSTRACT RNA-mediated silencing processes play a key role in silencing

of transposable elements, especially in the germ line, where piwi-interacting
RNAs (piRNAs) are responsible for suppressing transposon mobility and
maintaining genome integrity. We previously reported that the genome of
Adineta vaga, the first sequenced representative of the phylum Rotifera (class
Bdelloidea), is characterized by massive levels of horizontal gene transfer, by
unusually low transposon content, and by highly diversified RNA-mediated
silencing machinery. Here, we investigate genome-wide distribution of pi-
like small RNAs, which in A. vaga are 2531 nucleotides in length and have
a strong 5'-uridine bias, while lacking ping-pong amplification signatures.
In agreement with expectations, 71% of mapped reads corresponded to
annotated transposons, with 93% of these reads being in the antisense
orientation. Unexpectedly, a significant fraction of piRNAs originate from
predicted coding regions corresponding to genes of putatively foreign origin.
The distribution of piRNAs across foreign genes is not biased toward 3'-UTRs,
instead resembling transposons in uniform distribution pattern throughout the
gene body, and in predominantly antisense orientation. We also find that genes
with small RNA coverage, including a number of genes of metazoan origin, are
characterized by higher occurrence of telomeric repeats in the surrounding
genomic regions, and by higher density of transposons in the vicinity, which
have the potential to promote antisense transcription. Our findings highlight the
complex interplay between RNA-based silencing processes and acquisition of
genes at the genome periphery, which can result either in their loss or eventual
domestication and integration into the host genome.

13
 GENE TICS OF COMPLE X TR AITS

Genetical Genomics of Behavior: A Novel

Chicken Genomic Model for Anxiety Behavior
Martin Johnsson, Michael J. Williams, Per Jensen, and Dominic Wright
Genetics January 2016 202: 327340

EDITORS NOTE Domestic chickens are much less anxious than their wild
cousins, the red junglefowl. Johnsson et al. took advantage of this extreme
behavioral difference, along with the chickens compact genome and high
recombination rate, to identify genes underlying anxiety behaviors. They
identified ten potentially causal genes for anxiety that were also correlated
with mouse anxiety behavior and human psychiatric disorders, demonstrating
the potential of the chicken to serve as a model for understanding the genetic
underpinnings of human behavior.

ABSTRACT The identification of genetic variants responsible for behavioral

variation is an enduring goal in biology, with wide-scale ramifications, ranging
from medical research to evolutionary theory on personality syndromes.
Here, we use for the first time a large-scale genetical genomics analysis in
the brains of chickens to identify genes affecting anxiety as measured by
an open field test. We combine quantitative trait locus (QTL) analysis in 572
individuals and expression QTL (eQTL) analysis in 129 individuals from an
advanced intercross between domestic chickens and Red Junglefowl. We
identify 10 putative quantitative trait genes affecting anxiety behavior. These
genes were tested for an association in the mouse Heterogeneous Stock
anxiety (open field) data set and human GWAS data sets for bipolar disorder,
major depressive disorder, and schizophrenia. Although comparisons
between species are complex, associations were observed for four of the
candidate genes in mice and three of the candidate genes in humans. Using
a multimodel approach we have therefore identified a number of putative
quantitative trait genes affecting anxiety behavior, principally in chickens
but also with some potentially translational effects as well. This study
demonstrates that chickens are an excellent model organism for the genetic
dissection of behavior.

14
PECKING ORDER Siblings from the eighth generation of an
advanced intercross between White Leghorn chickens and red
junglefowl described in Johnsson et al. The hybrids show wide variation
in appearance and behavior. Photo: Dominic Wright.

15
 GENOME & SYSTEMS BIOLOGY

Genome-Wide Structural Variation Detection

by Genome Mapping on Nanochannel Arrays
Angel C. Y. Mak, Yvonne Y. Y. Lai, Ernest T. Lam, Tsz-Piu Kwok, Alden K. Y. Leung,
Annie Poon, Yulia Mostovoy, Alex R. Hastie, William Stedman, Thomas Anantharaman,
Warren Andrews, Xiang Zhou, Andy W. C. Pang, Heng Dai, Catherine Chu, Chin
Lin, Jacob J. K. Wu, Catherine M. L. Li, Jing-Woei Li, Aldrin K. Y. Yim, Saki Chan,
Justin Sibert, eljko Dakula, Han Cao, Siu-Ming Yiu, Ting-Fung Chan, Kevin Y. Yip,
Ming Xiao, and Pui-Yan Kwok
Genetics January 2016 202: 351362

EDITORS NOTE Whole-genome short-read sequencing is now routine and

affordable. But genomics still faces the major challenge of comprehensive
detection of structural variation. Mak et al. demonstrate genome-wide
identification of structural variation at 5-kb resolution without sequencing
through an approach called genome mapping. This method uses massively
parallel analysis of long, fluorescently labeled DNA molecules imaged on
nanochannel arrays. The authors generated genome maps for a trio from
the 1000 Genomes Project and showed the individuals have many more
structural variants than previously published, including some with the
potential to disrupt gene function.

ABSTRACT Comprehensive whole-genome structural variation detection is

challenging with current approaches. With diploid cells as DNA source and
the presence of numerous repetitive elements, short-read DNA sequencing
cannot be used to detect structural variation efficiently. In this report, we
show that genome mapping with long, fluorescently labeled DNA molecules
imaged on nanochannel arrays can be used for whole-genome structural
variation detection without sequencing. While whole-genome haplotyping is
not achieved, local phasing (across >150-kb regions) is routine, as molecules
from the parental chromosomes are examined separately. In one experiment,
we generated genome maps from a trio from the 1000 Genomes Project,
compared the maps against that derived from the reference human genome,
and identified structural variations that are >5 kb in size. We find that these
individuals have many more structural variants than those published, including
some with the potential of disrupting gene function or regulation.

16
 GENOME INTEGRIT Y & TR ANSMISSION

A Delicate Balance Between Repair and

Replication Factors Regulates Recombination
Between Divergent DNA Sequences in
Saccharomyces cerevisiae
Ujani Chakraborty, Carolyn M. George, Amy M. Lyndaker, and Eric Alani
Genetics February 2016 202: 525540

EDITORS NOTE Despite multiple lines of defense, non-allelic sequences can

undergo homologous recombination, rearranging the genome in potentially
harmful ways. To suppress single-strand annealing (SSA) between divergent
sequences, the Msh DNA mismatch recognition complex and Sgs1 helicase
bind to mismatches in heteroduplex DNA intermediates and trigger an
unwinding mechanism known as heteroduplex rejection. Chaktraborty et al.
identify new regulatory steps in heteroduplex rejection during SSA, showing
that tail clipping is a critical regulatory step in the rejection vs. repair decision.

ABSTRACT Single-strand annealing (SSA) is an important homologous

recombination mechanism that repairs DNA double strand breaks (DSBs)
occurring between closely spaced repeat sequences. During SSA, the
DSB is acted upon by exonucleases to reveal complementary sequences
that anneal and are then repaired through tail clipping, DNA synthesis, and
ligation steps. In bakers yeast, the Msh DNA mismatch recognition complex
and the Sgs1 helicase act to suppress SSA between divergent sequences
by binding to mismatches present in heteroduplex DNA intermediates and
triggering a DNA unwinding mechanism known as heteroduplex rejection.
Using bakers yeast as a model, we have identified new factors and regulatory
steps in heteroduplex rejection during SSA. First we showed that Top3-Rmi1,
a topoisomerase complex that interacts with Sgs1, is required for heteroduplex
rejection. Second, we found that the replication processivity clamp proliferating
cell nuclear antigen (PCNA) is dispensable for heteroduplex rejection, but is
important for repairing mismatches formed during SSA. Third, we showed that
modest overexpression of Msh6 results in a significant increase in heteroduplex
rejection; this increase is due to a compromise in Msh2-Msh3 function required
for the clipping of 3' tails. Thus 3' tail clipping during SSA is a critical regulatory
step in the repair vs. rejection decision; rejection is favored before the 3' tails are
clipped. Unexpectedly, Msh6 overexpression, through interactions with PCNA,
disrupted heteroduplex rejection between divergent sequences in another
recombination substrate. These observations illustrate the delicate balance that
exists between repair and replication factors to optimize genome stability.

17
 ME THODS, TECHNOLOGY, & RESOURCES

Rapid Short-Read Sequencing and Aneuploidy

Detection Using MinION Nanopore
Technology
Shan Wei and Zev Williams
Genetics January 2016 202: 3744

EDITORS NOTE MinION portable sequencers were designed for long

DNA fragments. Could repurposing them for short fragments enable rapid
sequencing for time-sensitive applications in office, field, and clinical settings?
Wei and Williams describe a library preparation and data analysis method to
test this hypothesis and demonstrate its clinical applicability by performing
sequencing in less than 4 hours to detect aneuploidy in prenatal and
miscarriage samples.

ABSTRACT MinION is a memory sticksized nanopore-based sequencer

designed primarily for single-molecule sequencing of long DNA fragments (>6
kb). We developed a library preparation and data-analysis method to enable
rapid real-time sequencing of short DNA fragments (<1 kb) that resulted in
the sequencing of 500 reads in 3 min and 40,00080,000 reads in 24 hr
at a rate of 30 nt/sec. We then demonstrated the clinical applicability of this
approach by performing successful aneuploidy detection in prenatal and
miscarriage samples with sequencing in <4 hr. This method broadens the
application of nanopore-based single-molecule sequencing and makes it a
promising and versatile tool for rapid clinical and research applications.

18
 ISLAND GUARD The unique Fonnis dog is a herd guardian endemic to the
island of Sardinia. Although these dogs vary widely in appearance, they all
share a wariness of strangers and a fierce guarding instinct. Analysis of 28 dog
breeds revealed that this regional variety has developed into a true breed through
unregulated selection for its distinctive behavior, and that its ancestors came from
the same geographic areas as Sardinias human migrants. Just as Sardinian people
have long provided a wealth of genetic insights to scientists, the canine natives
are an example of an isolated population that could prove a powerful resource for
finding genes that influence health and behavior. Photo: Luca Spennacchio.

Commonalities in Development of Pure Breeds and Population

Isolates Revealed in the Genome of the Sardinian Fonnis Dog
Dayna L. Dreger, Brian W. Davis, Raffaella Cocco, Sara Sechi,
Alessandro Di Cerbo, Heidi G. Parker, Michele Polli, Stefano P. Marelli,
Paola Crepaldi, and Elaine A. Ostrander
Genetics December 2016 204: 737755 19
 PERSPECTIVES

Hubby and Lewontin on Protein Variation in

Natural Populations: When Molecular Genetics
Came to the Rescue of Population Genetics
Brian Charlesworth, Deborah Charlesworth, Jerry A. Coyne, and Charles H. Langley
Genetics August 2016 203: 14971503

EDITORS NOTE In 1966, population genetics remained in a longstanding

and ultimately highly productive debate about the classical vs. balance
views of genetic variability. The publication of a pair of GENETICS papers by
John Hubby and Richard Lewontin shook up the field, revealing a surprisingly
high level of protein sequence variability in natural populations. To mark the
fiftieth anniversary of the papers and the hundredth anniversary of the journal,
Charlesworth et al. discuss these pioneering studies and their influence.

ABSTRACT The 1966 GENETICS papers by John Hubby and Richard

Lewontin were a landmark in the study of genome-wide levels of variability.
They used the technique of gel electrophoresis of enzymes and proteins to
study variation in natural populations of Drosophila pseudoobscura, at a
set of loci that had been chosen purely for technical convenience, without
prior knowledge of their levels of variability. Together with the independent
study of human populations by Harry Harris, this seminal study provided the
first relatively unbiased picture of the extent of genetic variability in protein
sequences within populations, revealing that many genes had surprisingly
high levels of diversity. These papers stimulated a large research program
that found similarly high electrophoretic variability in many different species
and led to statistical tools for interpreting the data in terms of population
genetics processes such as genetic drift, balancing and purifying selection,
and the effects of selection on linked variants. The current use of whole-
genome sequences in studies of variation is the direct descendant of this
pioneering work.

20
 POPUL ATION & E VOLUTIONARY GENE TICS

Natural Selection and Genetic Diversity in the

Butterfly Heliconius melpomene
Simon H. Martin, Markus Mst, William J. Palmer, Camilo Salazar, W. Owen McMillan,
Francis M. Jiggins, and Chris D. Jiggins
Genetics May 2016 203: 525541

EDITORS NOTE Most of what we have learned about the effects of

selection and drift in natural insect populations comes from studies of
Drosophila, which show evidence of rampant selection. Martin et al.
investigate genetic diversity and signatures of selection in Heliconius
butterflies, which differ from Drosophila in a number of wayssuch as smaller
and more stable population sizesthat might influence genomic patterns
of selection. The authors used resequenced genomes from 58 wild-caught
individuals of Heliconius melpomene and another 21 resequenced genomes
representing 11 related species. The results suggest that positive selection
is less pervasive compared to fruit flies, a fact that curiously results in very
similar levels of neutral diversity in these very different insects.

ABSTRACT A combination of selective and neutral evolutionary forces

shape patterns of genetic diversity in nature. Among the insects, most
previous analyses of the roles of drift and selection in shaping variation
across the genome have focused on the genus Drosophila. A more complete
understanding of these forces will come from analyzing other taxa that differ
in population demography and other aspects of biology. We have analyzed
diversity and signatures of selection in the neotropical Heliconius butterflies
using resequenced genomes from 58 wild-caught individuals of Heliconius
melpomene and another 21 resequenced genomes representing 11 related
species. By comparing intraspecific diversity and interspecific divergence, we
estimate that 31% of amino acid substitutions between Heliconius species
are adaptive. Diversity at putatively neutral sites is negatively correlated with
the local density of coding sites as well as nonsynonymous substitutions and
positively correlated with recombination rate, indicating widespread linked
selection. This process also manifests in significantly reduced diversity on
longer chromosomes, consistent with lower recombination rates. Although
hitchhiking around beneficial nonsynonymous mutations has significantly
shaped genetic variation in H. melpomene, evidence for strong selective
sweeps is limited overall. We did however identify two regions where distinct
haplotypes have swept in different populations, leading to increased population
differentiation. On the whole, our study suggests that positive selection is less
pervasive in these butterflies as compared to fruit flies, a fact that curiously
results in very similar levels of neutral diversity in these very different insects.

21
 POPUL ATION & E VOLUTIONARY GENE TICS

Effects of Linked Selective Sweeps on

Demographic Inference and Model Selection
Daniel R. Schrider, Alexander G. Shanku, and Andrew D. Kern
Genetics November 2016 204: 12071223

EDITORS NOTE Patterns of genetic variation within a species contain clues

about demographic events such as changes in population size. However,
adaptation can often result in similar patterns. Schrider et al. demonstrate
that demographic inference methods that assume genetic variation is not
influenced by natural selection produce erroneous results when applied
to populations experiencing adaptation. These results suggest that
demographic studies conducted in many species may have exaggerated the
extent and frequency of population size changes.

ABSTRACT The availability of large-scale population genomic sequence

data has resulted in an explosion in efforts to infer the demographic histories
of natural populations across a broad range of organisms. As demographic
events alter coalescent genealogies, they leave detectable signatures in
patterns of genetic variation within and between populations. Accordingly,
a variety of approaches have been designed to leverage population genetic
data to uncover the footprints of demographic change in the genome. The
vast majority of these methods make the simplifying assumption that the
measures of genetic variation used as their input are unaffected by natural
selection. However, natural selection can dramatically skew patterns of
variation not only at selected sites, but at linked, neutral loci as well. Here we
assess the impact of recent positive selection on demographic inference by
characterizing the performance of three popular methods through extensive
simulation of data sets with varying numbers of linked selective sweeps.
In particular, we examined three different demographic models relevant
to a number of species, finding that positive selection can bias parameter
estimates of each of these modelsoften severely. We find that selection
can lead to incorrect inferences of population size changes when none have
occurred. Moreover, we show that linked selection can lead to incorrect
demographic model selection, when multiple demographic scenarios are
compared. We argue that natural populations may experience the amount of
recent positive selection required to skew inferences. These results suggest
that demographic studies conducted in many species to date may have
exaggerated the extent and frequency of population size changes.

22
 STATISTICAL GENE TICS & GENOMICS

Local Joint Testing Improves Power and

Identifies Hidden Heritability in
Association Studies
Brielin C. Brown, Alkes L. Price, Nikolaos A. Patsopoulos, and Noah Zaitlen
Genetics July 2016 203: 11051116

EDITORS NOTE Genome-wide association studies (GWAS) typically

investigate each SNP in isolation of all others for association with a phenotype
of interest. Brown et al. describe an overlooked phenomenon, linkage
masking, wherein linkage disequilibrium between SNPs masks their signal
under standard tests, preventing their discovery in GWAS. They test pairs of
nearby markers to improve power at loci harboring multiple causal variants,
including linkage masked SNPs. This method outperforms the standard
marginal association method, providing further evidence that disease loci
frequently bear more than one causal mutation.

ABSTRACT There is mounting evidence that complex human phenotypes

are highly polygenic, with many loci harboring multiple causal variants, yet
most genetic association studies examine each SNP in isolation. While this
has led to the discovery of thousands of disease associations, discovered
variants account for only a small fraction of disease heritability. Alternative
multi-SNP methods have been proposed, but issues such as multiple-
testing correction, sensitivity to genotyping error, and optimization for the
underlying genetic architectures remain. Here we describe a local joint-
testing procedure, complete with multiple-testing correction, that leverages a
genetic phenomenon we call linkage masking wherein linkage disequilibrium
between SNPs hides their signal under standard association methods. We
show that local joint testing on the original Wellcome Trust Case Control
Consortium (WTCCC) data set leads to the discovery of 22 associated loci,
5 more than the marginal approach. These loci were later found in follow-
up studies containing thousands of additional individuals. We find that
these loci significantly increase the heritability explained by genome-wide
significant associations in the WTCCC data set. Furthermore, we show that
local joint testing in a cis-expression QTL (eQTL) study of the gEUVADIS data
set increases the number of genes containing significant eQTL by 10.7%
over marginal analyses. Our multiple-hypothesis correction and joint-testing
framework are available in a python software package called Jester, available
at http://github.com/brielin/Jester.

23
 RE VIE W COLLECTIONS

YeastBook, FlyBook, and WormBook are comprehensive review

collections presenting the current state of knowledge in yeast,
Drosophila, and C. elegans research. Published by GENETICS in
partnership with each model organism community, these ongoing
collections are edited by a dedicated team of experts and cover a
broad range of topics, including methods, genetics, evolution, cell
biology, development, and much more.

YeastBook FlyBook WormBook

Editor-in-Chief Editor-in-Chief Editor-in-Chief

Alan G. Hinnebusch
National Institutes of Health
Lynn Cooley Iva Greenwald
Yale University Columbia University
Co-Editor-in-Chief
John R. Carlson
Yale University
Co-Editor-in-Chief
R. Scott Hawley
Stowers Institute for
Medical Research
Co-Editor-in-Chief
Therese Ann Markow
University of California,
San Diego

24
GENOME GIANT At 31 billion base pairs, the genome of the towering
sugar pine is ten times the size of the human genome. The sugar pine genome
is the largest fully sequenced to date. Along with the sugar pine transcriptome
published in G3, the genome analysis revealed candidate genes for resistance to
the white pine blister rust that threatens this iconic species and its ecosystem.
Stevens et al. Genetics 204: 16131626. Painting: Dean Davis, a retired US Forest
Service employee. This painting was based on a tree on Thompson Ridge in an
area heavily blighted by blister rust. Many of the initial selections for white pine
blister rust resistance were made nearby in the 1950s and 60s.

25
Why publish in GENETICS & G3?
Fast Decisions, Fast Access
Tired of reformatting manuscripts? We welcome initial submissions in any format
and impose no limits on length, figures, or supplemental information. Plus, we
answer pre-submission inquiries within days, and can even fast-track handling in
some circumstances.

Time to first decision? About a month.

Initial call on whether to send for review takes just days.

Within days of initial manuscript submission, we will let you know whether the
manuscript will be sent for review. For reviewed manuscripts, the editors strive
to reach a decision in less than 30 days. For revised papers, more than 90% are
accepted without an additional round of reviews.

Average time from submission to acceptance is

less than 8 weeks.

High-Quality Review & Peer Editors

Ever struggled with an unclear decision letter or reviews that dont give you a clue
about where to start your revision? Our journals are known for providing insightful
and helpful reviews.

At least two editors consult on every decision.

Your manuscripts will be handled by practicing scientists like you, who understand
from experience what it takes to tell a significant story, to create a useful method
or resource, or to extract meaning from large datasets. Rather than simply tally
reviewer votes, your editor synthesizes the reviews into a single, clear decision
letter that offers guidance and explains rationales for all decisions, helping to
improve your papers impact. Still have questions? Contact the editorial office or the
editor. Speak with a real person wholl be up front with you.

Consolidated, clear feedback from your editor.

Decision letter offers specific guidance for revisions.
 Sister Journals, One-Touch Transfer
If you submit a manuscript to GENETICS that reports high-quality and
useful findingsbut lacks the broad appeal, significance, or novelty of
a published GENETICS articleyou may be offered a transfer to G3.
This seamless process either guarantees review at G3, or G3 editors
will use the GENETICS reviews to offer a decision within days.

After Acceptance
Within days, manuscripts are published Early Online, indexed in
PubMed, and available to colleagues. You may be selected for
highlights in GENETICS, cover art, press releases, promotion on
GSAs Genes to Genomes blog, social media, e-news, and other
outreach. We enhance discovery and use of your research, which in
turn increases its impact.

Community Support
Our journals are run by and for scientists under the aegis of the Genetics Society
of America. GSA represents us, advocates for us, convenes us, publicizes us,
provides educational resources, and fosters our work.
GENETICS and G3 are committed to integrating with community resources. Weve
long supported the use of preprints, and in 2014 we partnered with Cold Spring
Harbor Laboratories to enable seamless deposits of manuscripts from our submission
systems to bioRxiv, and vice versa. Articles feature links to model organism databases
like SGD, FlyBase, WormBase, and FungiDB. We provide custom templates for
authors who use LaTeX, saving them time at submission. So you can assess your
research impact in multiple ways, each paper features article level metrics that show
mentions on Twitter, Facebook, in the popular press, plus other alternative metrics.

Access to Data
Our data policy, instituted in 2009, requires that all primary data and
source code associated with the papers findings must be publicly
available, either as supplemental information or in a public repository
like Dryad, FigShare, and GenBank. Besides providing everything
needed for replication, this policy allows your research to have the greatest
possible impact and ensures your findings will be used for years to come.

Not sure if your work is a good fit for our journals?

We welcome pre-submission inquiries!