and the Genome:
A Complex and Evolving Tale
Marianne J. Legato, M.D., F.A.C.P.
Professor of Clinical Medicine, Columbia University
Director, Partnership for Gender
Specific Medicine at
Adjunct Professor of Medicine, Johns Hopkins
The past twenty years have witnessed
a profound series of changes in our approach
to and our achievements in biomedical investigation.
As a result, we have a radically new view
of normal human biology and the
pathophysiology of disease and indeed,
of the nature of life itself.
Instead of “what are the differences
between male and female?”,
many scientists are asking:
does it mean to be human?”
Made men normative
Paradoxically, there has not
been a systematic consideration
Not grappled with the
extraordinarily difficult and
most important issue of teasing
out what characteristics are
wired as a result of
biological sex and which are
the consequence of social
forces and environment.
Critics of the biomedical model
have demonstrated that:
J. Lorber. Gender and the Social Construction of Illness. Sage
Publications, Thousand Oaks, CA 1997. Quoted by Bird CE in
What Influences “Health”?
Biomedical and sociologic experts often disregard and even disparage
each other, particularly when funding is scarce.
about health influence practice (The notion that women
are relatively immune to coronary artery disease is still deep seatd in
health behaviors of men and women
the level of attention given to preserving male and female health
the societal roles expected of males and females.
These patterns may shift over time.
Sterling: without absolute social equality we cannot know
the absolute differences between men and women.
What Influences Biomedical
Previous experiences and
2010: How Far Have We Come
and Where are We Now?
We are more aware of the extent and complexity
sex and gender specific properties
We are exploring how the intricate dance
between the genome, hormones and the
environment creates the
We are inserting mechanical components into
humans, including into their brains. We are also
creating completely mechanical entities;
capable of heretofore unimagined complex
The new age of
our understanding of what constitutes life. For
the first time in the history of the world we have
the power to generate new forms of life,
themselves capable of reproduction.
Modern Scientific Investigation:
1940’s to 1980’s
The Bikini View of Women’s Health
The New Science of Gender
And the Beginning of the Genomic Era
Some Important Issues
what is hard
into the organism by virtue of biological sex and
what is the result of the impact of other factors on
What is the impact of biological sex on gene
Given the complexity of how the phenotype is
determined, how powerful/useful will the
delineation of an
individual’s genome be
predicting disease and in choosing therapy?
To what extent will mechanical parts augment
human abilities? What does it mean to be ‘human’?
What role will
play in the nature of
life on this planet?
wired into the organism by
virtue of biological sex and
what is the result of the impact of
on the phenotype?
(It is impossible to separate the
organism from its experience.)
“There is no gene
controlled inheritable trait that cannot be
altered by the environment…Humans enter the world as a
progress…Nature/nurture is not an either/or duality
but, rather, represents a
type of complementarity.”
Leonard Schlain. Sex. Time and Power. Penguin Books. New York. 2003.
The Complex Dance Between the Genome
How Environmental Factors Impact
Environmental factors act by
mutating promoter and coding regions of genes
modifying CpG methylation at critically labile genomic
Waterland R and Jirtle R. Nutrition 20:63.2004)
Epigenetic mechanisms include chromatin folding and
attachment to the nuclear matrix, packaging of DNA
around nucelosomes, covalent modifications of histone tails
and DNA methylation.
(Dolinoy DC and Jirtle RL.Environ. Mol
Regulatory small RNA’s and micro RNA’s impact gene
(Matzke M and Birchler J. Nat Rev Genet 6:24.2005)
Changes the Brain
Neural changes associated with
: increase in brain
size, cortical thickness, neuron size, dendritic branching, spine density,
synapses per neuron and glial numbers.
(Kolb B and Whishaw IQ. Annu Rev
Modulation of Experience
neuronal loss and dendritic growth: an area of controversy.
essential to sex
specific development of the brain and to
maintain the sex
specific characteristics of the brain throughout life.
Stewart J and Kolb B. Behav.Neural Biol.49:344.1988 and Brain Res.654:149. 1994.)
chronic excess of glucocorticoids is toxic to neurons.
Sapolsky RM. Stress,
the Aging Brain and Mechanisms of Neuronal Death. MIT Press. 1992)
Early life experience and major stressful life events produce
dysregulation of serotonergic systems
(Gardner LK et al. Brain Research
The White House announces the completion
of a rough draft of the human genome.
April 14, 2003:
The Human Genome Project announces
a much more complete and accurate version.
The New World of Genomic Science
Gender and the Genome:
Why do we have two sexes?
How do they differ?
Which is hardier?
Sexual Dimorphism is Achieved Not
Only by Gonadal Hormones but by the
Direct Effect of X and Y Genes.
The discovery of the gynandromorphic
zebra finch: this bird has male plumage
and a testis on the right side of the body
and female plumage and an ovary on the left side.
the brain was also sexually dimorphic; brain
tissue on the right was genetically male and
that on the left female. The hormonal milieu
of the bird was obviously homogeneous.*
*Agate RJ et al. Proc. Natl. Acad Sci USA100:4873 2003
The X chromosome*
Contains 1,098 genes; only 4% of all human genes:
gene density is low and gene length is lower than any other
of the chromosomes annotated to date. (Furthermore, only
33% of the chromosome is transcribed.)
Only 54 of these genes have functional homologues on the
Many of the genes that have to do with intelligence may be
located on the X chromosome and may be closely linked
with a gene dictating preference for intelligent males.
Almost 10% of diseases with a mendelian pattern of
inheritance are X
*Ross MT et al. The DNA sequence of the human X chromosome. Nature 434:325
“Functional or developmental themes
been ascribed to whole chromosomes in eukaryotes.
instead, individual chromosomes appear to contain motley
assortments of genes with extremely heterogeneous patterns
of developmentally regulated expression.
We speculated that the human Y chromosome might be a
functionally coherent exception…”
*Lahn BT and Page DC. Functional Coherence of the Human Y chromosome
The Y Chromosome:
a New View
The Y Chromosome:
Revising the Wasteland Model*
It is an unique chromosome
Common ancestry and persistent relationship with the X chromosome
Present only in males
Does not combine with its partner along 95% of its length (called the NRY
recombining portion of the Y chromosome
Tendency of its genes to degenerate during evolution
Unique coherence of gene content
Contains 78 genes (almost double the previously known tally) which make up <1% of the
They encode only 28 distinct proteins.
The Y chromosome
can repair itself as a result of its palindromic structure.
copy of each of the genes they contain exists at each end of the sequence.
Lahn BT and Page DC. Functional Coherence of the Human Y Chromosome. Science 278:675
Male Driven Evolution*
Almost all new mutations are derived from the
(Makova KD and Li WH. Nature 416:624
Oocytes spend most of their lives in relative dormancy .
Sperm are produced in huge numbers and have much
higher metabolic requirements.
Male: female mutations in primates is about 3
Mutations result from
Variability in the male germ line creates the genetic
diversity that fuels the evolutionary process.
Aitken RJ and Krausz C. Oxidative stress, DNA damage and the Y chromosome. Reproduction
Given the complexity of how the
phenotype is determined, how
powerful/useful will the delineation of
individual’s genome be
disease and in choosing therapy?
Skepticism about genomics runs high….
Some …perceive genomics research as a low
investment at best and as a dangerous
opportunity cost at worst, which undercuts efforts
to address social and environmental causes
of ill health.”
Combining Genomics with Epidemiology:
Balancing Population Based with Individually
Targeted Prevention/Treatment Strategies.
Is increasing attention to genomics
useful for the
Will it widen the gap between richer and poorer members of society?
Will it reinforce racial stereotyping?
Will it lead researchers to miss factors that contribute to disparities more
substantially than genomics?
The new science of
human genome epidemiology
Prevalence of gene variants in different populations
Magnitude of disease risk associated with gene variants
Magnitude of disease risk associated with gene
gene and gene
Validity and effectiveness of genetic tests for screening and prevention.
Khoury MJ et al. Am J Prev Med 33(4).310
“The question of how genes are defined
and regulated is deceptively simple.
The emerging picture of gene regulation
depicts interdependent layers and webs
of control consisting of interactions of DNA with
regulatory proteins and RNA molecules that are
akin to the interactions that occur
in computer circuitry.”*
Feero WG et al. N Engl. J. Med 362:21.May 27, 2010
The Human Genome Project:
Is It the Holy Grail?*:
The Notion of Biological Determinism
“The assumption that genes are the carrier of our destiny...
explanations to behavior above all
others and, in so doing,
allocates other causes such as
environment to subsidiary roles
Genes are not the determinant mechanism in a biological
but part of an interaction between the genes and
the organism as a whole.
a more complex and less popular view, which
maintains that reductionism is inadequate to explain living
systems. It maintains that one must look at the
organizational structure of the organism, not just its
Morse A. Searching for the Holy Grail: the Human Genome Project and Its Implications.J Law
“The idea that the human genome
can be the Rosetta Stone for
disease ignores physical, chemical
and environmental factors.*
Keller EF. Master Molecules, in ARE GENES US? Carl F. Cranor ed. 1994.
What is the impact of
on gene expression?
The Genetic Gender Gap: The
Sexually Dimorphic Gene*
Thousands of genes showed sexual dimorphism
in liver, adipose
and muscle; hundreds of genes were sexually dimorphic in
These differences are
highly tissue specific
; thousands of genes
identified were involved in tissue
specific biological functions
and/or pathways relevant to common diseases and showed
specific chromosomal enrichment.
Only 27 genes showed consistent direction , i.e. all female or all
male biased in all tissues.
A significant portion of sexually dimorphic genes are located on
the sex chromosomes, but some are carried on autosomes as
*Yang X et al. Tissue
specific expression and regulation of sexually dimorphic
Genes in mice. Genome Research.16:995
Sex Impacts Gene Expression*
“We saw striking and measurable differences
in more than half of the genes’ expression pattern
between males and females. We didn’t expect that.
no one has previously demonstrated this genetic
gender gap at such high levels.”**
*Yang et al. Genome. 2006
**Thomas Drake, C0 investigator
Is manipulating the genome
interfering with evolution or
by definition, a continuation
of the process?
Taking genes out and
specimens capable of
Giving us an increasingly
precise picture of who we
are and the possibility of
Evolution is no longer
With the advent of
of created life.
Engineering the characteristics of new
(human?) beings prepared for specific
functions (like war, for example)
Prolonging the life span indefinitely
Creating new biological systems capable
of reproduction (and if this is so, also
capable themselves of evolution)
Genomic Science and Sex
Will it be an advantage to retain
If we eliminate biological sex in
new forms of life before we
understand the nature and
extent of its expression on
genes, what will be the
consequences to form and
Does the study of the impact of
sex on gene expression deserve
more attention? Genomic
scientists are not always
considering the impact of
biological sex on their data.
“If the molecular, cellular, and genetic machinery
used to conceive, develop, and operate a human
were designed rather than the result of evolution,
humans would be different
and life would look different.”*
*Olshansky et al. What if Humans were Designed to Last?
The Scientist. 21(3).28
What are scientists
Consider the Impact Of
Genomic Science On
The nature and number of living beings
The redistribution of power (planned and
I chide Goldblatt* for the
he and the
Defense Sciences Office displayed
in not thinking its plans to enhance
humans would arouse controversy
t it occur to anybody that you
were playing with fire?
(in Radical Evolution)
Michael Goldblatt, former head of the Defense Science Office
What Scientists are Saying
We are changing the rate and
mechanisms of the evolution of living
If there is a choice between preserving
the earth in a viable state or continuing
the human race, we will probably opt to
continue the race.
My guess is that if the question of human extinction is
ever posed clearly, people will say that it’s all very well to
say we’ve been a part of nature up to now, but that at this
turning point in the human race’s history, it is surely essential that
we do something about it; that we fix the genome to get of rid
of the disease that’s causing the instability, if necessary, we clone
people known to be free from the risk, because that’s the only way
in which we can keep the human race alive.
A still, small voice may at that stage ask, but right does the
human race have to claim precedence for itself. To which my
guess is the full
throated answer would be, sorry, the human
race has taken a decision, and that decision is to survive. And,
if you like, the hell with the rest of the ecosystem.”
Sir John Maddox,
Former editor of
The ability to create living
organisms from inert chemicals.
These new entities will probably
be capable themselves of reproduction
and of evolution into new
Venter’s group has just reported the design, synthesis
and assembly of a genome and its transplantation into
a recipient cell to create new cells
that are controlled
only by the synthetic chromosome.*
Gibson DG et al. Sciencexpress./www.sciencexpress.org/20 May 2010/Page 1.
urges Presidential Commission for the Study of Bioethical Issues to
focus on the research: “This development raises the prospect of important
benefits….at the same time it raises genuine concerns…”.
: “This milestone and many like it should be
synthetic myobacterium is not changed from the
wild state in any fundamental sense. Printing out a copy of an ancient text isn’t
the same as understanding the language.”
: “Venter and his colleagues have shown that the material world
can be manipulated to produce what we recognize as life…Christianity, Islam
and Judaism, among other religions, have maintained that a soul constitutes
the explanatory essence of at least human life….All of these…views are cast
into doubt by the demonstration that life can be created from non
: “Venter…calls this ‘going from reading our genetic code
to the ability to write it.” It may sound scary, but there is no guarantee that
what will be written will make sense.”
Ever since the discovery of
nuclear fission, the possibility of
powerful explosives based on it
had been very much in my mind,
as it had in that of many other
physicists. We had some
understanding of what this might
do for us in the war, and how much
it might change the course of
“I am become death,
destroyer of worlds.”
Professor of Genetics at Harvard Medical School
Director of the Center for Computational Genetics.
synthetic biology shares the potential…to generate
new entities that reproduce and evolve at will.
Whether we believe that these are immediate, distant
or imaginary threats, the concerns are real….in addition
to a code of professional ethics for synthetic biologists,
we need to watch for the rare cases where they transgress.”
Given the momentum and international character
of research in synthetic biology, it is already
too late to impose a moratorium, if indeed one
was ever contemplated.”*
Tucker and Zilinskas: The Problems and Perils of
Synthetic Biology. In The New Atlantis. A
Journal of Technology and Society.
Prometheus, who gave men fire.
What Are Areas of Special Interest
As We Go Forward?
specific lens on men
, so that we can better
understand their greater vulnerability compared with women.
Expanding the current science of gender
specific medicine and
its value in clinical practice.
Urging the exploration of the
impact of biological sex
on both the
naturally occurring and synthetically created/altered genome.
between jurists, ethicists and scientists
about the legal and moral implications of genomic science and