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OBITUARY
Mary Lyon: A Tribute
Sundeep Kalantry1,* and Jacob L. Mueller1,*
Figure 1. Lyon at the 1985 Cold Spring Harbor Symposiumon Quantitative Biology Meeting ‘‘Molecular Biology ofDevelopment’’ in 1985Photo courtesy of the Cold Spring Harbor Symposia on Quantita-tive Biology Collection of the Cold Spring Harbor LaboratoryLibrary and Archives.
Mary Lyon passed away on Christmas Day, 2014, at the
age of 89. Best known for the X-chromosome-inactivation
hypothesis, Mary Lyon was a pioneering geneticist whose
findings and syntheses have left a lasting imprint on our
understanding of mammalian development and disease
(Figure 1). She was the recipient of the 1986 William Allan
Award,1 the most prestigious prize given by the American
Society of Human Genetics.
Mary Lyon was born in 1925 in Norwich, England. Her
interest in biology arose while she was a secondary school
student at King Edward VII School in Birmingham. Later,
despite difficulties posed as a result of air raids and a scar-
city of specialist teachers duringWorldWar II, Lyon passed
the University of Cambridge entrance examination and
entered Girton College at Cambridge. Lyon’s admission
into Cambridge was all the more impressive because at
the time, women constituted only ~10% of the entire stu-
dent populace. At Cambridge, Lyon studied zoology and
graduated in 1946 with a ‘‘titular’’ degree, given that
women were not considered official members of the uni-
versity then (in 1998, in a special ceremony, Cambridge
awarded her a B.A.). It was as a student at Cambridge that
Lyon became intrigued by genetic regulation as the basis
of embryonic development. Lyon worked with R.A. Fisher,
a professor of genetics at Cambridge University and co-
founder of the field of population genetics, to pursue a
Ph.D. in the growing discipline of mouse genetics. Finding
her experience there unsatisfactory, Lyon transferred to the
University of Edinburgh and joined the Institute of Animal
Genetics, headed by the eminent embryologist Conrad H.
Waddington. After completing her Ph.D. in Edinburgh
with Douglas Falconer in 1950, she stayed on to work in
Toby Carter’s group to investigate the heritable mutagenic
effects of radiation through mice. In search of more mouse
space, in 1954 Carter moved his group to the Medical
Research Council (MRC)-funded Radiobiology Unit at
Harwell. Although Lyon’s studies on mutations induced
by radiation in mice garnered much interest, her studies
in developmental genetics were what had a lasting impact.
The abundance of radiation-induced and spontaneously
arising mouse mutants at MRC Harwell dovetailed with
Lyon’s interest in developmental genetics. In fact, one
such mutant strain, mottled,2 was instrumental in Lyon’s
formulation of the X-inactivation hypothesis.3 The
mottled mutant phenotype, paradoxically, arose in a
male. Whereas some cells in the mottled male carried the
1Department of Human Genetics, University of Michigan Medical School, An
*Correspondence: [email protected] (S.K.), [email protected] (J.L.M.)
http://dx.doi.org/10.1016/j.ajhg.2015.09.002. �2015 by The American Societ
The Americ
mutant allele, others harbored the wild-type allele. As a
result of transmission of either the normal or the mutant
allele by this male only to his daughters, Lyon reasoned
that the male was mosaic for an X-linked gene.2,3 For
the mutant allele to be transmitted, she inferred that it
arose before the germline was specified, during early
embryogenesis. She further surmised that a similar logic
might underlie the mosaicism in the mottled daughters
of this male—the two types of colored patches in the
coat of the mottled females arose as a result of expression
of one or the other allele.3
n Arbor, MI 48109, USA
y of Human Genetics. All rights reserved.
an Journal of Human Genetics 97, 507–511, October 1, 2015 507
Mary Lyon combined a keen eye for analyzing her own
mice with an expert’s command of the literature. She
knew that female mice heterozygous for other sex-linked
mutations also showed a variegated coat color pattern.3
Lyon was also aware that XO female mice were viable,4
so only one X chromosome was essential in females.
Finally, Mary Lyon was familiar with Susumu Ohno’s
extrapolation that one X chromosome in diploid females
was the darkly staining body5 that Barr and Bertram had
previously found to characterize female nuclei.6 Ohno in-
terpreted this heteropyknotic X chromosome as ‘‘geneti-
cally inert’’ heterochromatin but left open the possibility
that ‘‘heteropyknosis alternates between the two X’s in a
female somatic nucleus.’’7
Lyon combined these pieces of information to predict
that one of the two X chromosomes in female mammals
is transcriptionally inactivated during early embryogen-
esis.3 Moreover, once inactivated, replicated copies of the
inactive X chromosome would be stably maintained as
inactive. These two ideas formed the basis of the Lyon
hypothesis, which has since been amply experimentally
validated. That one of the two X chromosomes in a female
cell becomes inactivatedwhile the other remains active and
that both faithfully maintain their transcriptional states
through many cell-division cycles have made X inactiva-
tion a paragon of epigenetic inheritance. As a testament
to Lyon’s extraordinary insight, the briefmonograph expli-
cating her hypothesis published in 19613 has garnered
>3,100 citations, many of which are in the current year.
Lyon stayed at Harwell for the duration of her career,
during which time it became a hotbed of mouse genetics.
Applying advances in cytogenetics, Lyon and her col-
leagues at Harwell, most notably Tony Searle and Bruce
Cattanach, began dissecting how X inactivation occurs.
Searle and Cattanach had characterized X-autosome trans-
locations in mice generated in chemical or radiation muta-
genesis experiments.8,9 Contrary to the random pattern of
inactivation normally found in somatic cells, these mutant
strains often displayed absolutely biased inactivation of
either the wild-type X chromosome or the mutant X in
females.10,11 Whether and which of the two chromosomes
was inactivated in heterozygotes could be cytologically
inferred because of differences in size between the two
X chromosomes.10,11 Using these and similar X-autosome
translocations, Lyon and colleagues proposed that a
segment on the X chromosome was required for X inacti-
vation—the so-called X-inactivation center (Xic).12–15
Eventually, the long non-coding RNA Xist (inactive X
specific transcript) was discovered within the human
Xic.16,17 Xist plays an essential role in the execution of
X chromosome inactivation.18–20
Lyon also collaborated with the pioneering embryologist
Richard Gardner at nearby Cambridge to assess when dur-
ing development X inactivation begins in mice.21 She also
delved into how a female cell can distinguish between
two X chromosomes to target one for inactivation through
a series of experiments with parthenogenetic embryos in
508 The American Journal of Human Genetics 97, 507–511, October
collaboration with Matthew Kaufman, also at Cam-
bridge.22,23 These studies brought to the fore Lyon and
Gardner’s trainee Sohaila Rastan, who then went on to
herself make seminal contributions in X inactivation. Ra-
stan collaborated with Elizabeth Robertson to considerably
narrow the critical Xic interval and provide a model of
how the cell counts its X chromosome complement,24,25
a landmark body of work that continues to influence
X-inactivation enthusiasts. In essence, the confluence of a
veritable who’s who of mouse genetics and embryology
in the small sphere of Harwell, Oxford, and Cambridge
resulted in groundbreaking insights into the process of
X inactivation—where Lyon served as the fulcrum and a
synthesizing force.
With the same clarity she brought to the understanding
of X inactivation, Lyon elucidated one of the most
perplexing anomalies in mouse genetics, the t-complex.
Later found to map to chromosome 17, the t-complex
engendered much interest because of the diversity of
developmental defects associated with this region of the
genome.26 Originally defined by mice harboring short
tails, t-complex mutations also resulted in embryonic
lethality, transmission ratio distortion, and male sterility.
In the 1940s, mutations in a single locus (brachyury [T])
were thought to contribute to an array of ‘‘t-alleles,’’27
which caused homozygous embryonic lethality. Lyon
was attracted to T because of its apparent high rate of mu-
tation and also because recombination is suppressed across
the T genomic region, both of which she thought could
improve the understanding of radiation-induced muta-
tions. To better understand these two phenomena, Lyon
crossed a series of naturally occurring t-alleles to labora-
tory-derived mouse mutants with visually discernable phe-
notypes, such as the short-tail mutant T and the hair-loss
mutant tufted.28 Lyon discovered rare recombinants be-
tween T and tufted, which uncoupled t-lethal mutations
from loci that caused transmission ratio distortion.29
Thus, she was able to show that the t locus is composed
not of a single gene but of multiple genes,30 a controversial
proposition at the time but one that has withstood the
test of time. The ‘‘t-alleles’’ represent a collection of genes
with distinct sets of mutations across >12 cM, which led
to the revised naming of the genomic segment as the
t-complex and its mutant forms as the t-haplotypes.
Spurred on by the fact that the t-complex is composed of
multiple genes, Lyon postulated that several genetically
separable loci are responsible for transmission ratio distor-
tion and male sterility.31 Mapping even a single causative
mutation in a large region that displays suppressed recom-
bination, as a result of a series of inversions, is most
geneticists’ nightmare. Nevertheless, Lyon forged ahead
and was able to genetically disentangle the t-complex to
propose that a single responder and at least three distorter
genes contribute to transmission ratio distortion32 and
male sterility.33 Her model of how the responder and dis-
torters work together to contribute to transmission ratio
distortion has subsequently been molecularly confirmed
1, 2015
Figure 2. Lyon Receiving the Pearl Meister Greengard Prize atRockefeller University in 2006Photo courtesy of Eric Weiss and Rockefeller University via JuliaBlackburn.
Figure 3. At the 2004 Commissioning of the Mary Lyon Centreat the MRC Harwell Research Laboratories, Dr. Lyon Standsalongside a Portrait of Herself with Mouse Cages Painted byDr. Lizzie BurnsReproduced with permission from the Medical Research Councilof the UK.
by Bernhard Herrmann’s laboratory with the identifica-
tion of the responder34 and three distorter genes.35–37
The wealth of genetic data on the t-complex also
facilitated cloning of T, the first gene to be positionally
cloned in mice and one that is essential for mesoderm
formation.38
Lyon’s elucidation of t-complex genetics and biology
was a true testament of her love of mammalian genetics
and development, considering the complexities of its
genomic architecture and the diversity of phenotypes.
With her incisiveness and knowledge of genetics, Lyon
simplified the structure and function of the t-complex,
both of which had stymied scientists for years. The t-com-
plex continues to harbor many secrets, but insights from
Lyon’s work were what laid the foundation for future prog-
ress in the field.
In addition to contributing to our understanding of
X inactivation, the t-complex, and beyond, Mary Lyon
served as the editor of Mouse News Letter, as well as its
successor, Mouse Genome, from 1956 to 1970. In this
community resource, Lyon and colleagues compiled the
emerging mouse mutation mapping data. In effect, Lyon
was a walking encyclopedia of the mouse genome, much
before the advent of computer databases.
Although quiet and pensive, on a personal level Mary
Lyon was considered warm and was interested in the
well-being of her friends and colleagues and their families.
The Americ
She was an inspiration to and a supporter of young scien-
tists especially. Her colleagues recall that she was humble
and unassuming but wouldn’t hesitate to point out ideas
borne of faulty logic.
Mary began her scientific career at an impossibly high
level and, remarkably, sustained it as such thereafter. For
her accomplishments, she was the recipient of many
honors: elected fellowship of the Royal Society (1973); the
Royal Medal (1984), the Royal Society’s most prestigious
honor; elected foreign membership in the US National
Academy of Sciences (1979); the Wolf Prize in Medicine
(1997); theMarchofDimes Prize inDevelopmental Biology
(2004); and the Pearl Meister Greengard Prize (2006),
awarded each year to outstanding female scientists by
the Rockefeller University (Figure 2). She was awarded
honorary doctorates from the Massachusetts Institute of
Technology and Princeton University. Earlier this year,
Lyon was also awarded a posthumous honorary doctorate
byRockefellerUniversity. Last year, theUKGenetics Society
an Journal of Human Genetics 97, 507–511, October 1, 2015 509
created the Mary Lyon medal to be awarded annually for
outstanding research in genetics. In 2004, Harwell inaugu-
rated the Mary Lyon Centre, an international facility for
mouse genetics and genomics resources, a fitting tribute
to Lyon’s immense scientific contributions (Figure 3).
Acknowledgments
We are indebted to a number of individuals who provided helpful
comments and biographical information. These include Mary
Lyon’s sister Julia Blackburn, Sir Richard Gardner, Bernhard
Herrmann, Sohaila Rastan, Elizabeth M.C. Fisher, Jo Peters, and
Steve Brown.
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