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: kalantry@umich.edu (S.K.), jacobmu@umich.edu (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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3. Lyon, M.F. (1961). Gene action in the X-chromosome of the

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4. Welshons, W.J., and Russell, L.B. (1959). The Y-Chromosome

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