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Hidden Meanings in Our Genomes–and What to Do with Mendel


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Gregor Mendel in textbooks: should he stay or should he go now? (Credit: Natl Library of Medicine)

Gregor Mendel in textbooks: should he stay or should he go now? (Credit: Natl Library of Medicine)

Summer reading for most people means magazines, novels, and similar escapist fare, but for me, it’s the American Journal of Human Genetics (AJHG). Perusing the table of contents of the current issue tells me what’s dominating this post-genomic era: information beyond the obvious, a subtext hidden within the sequences of A, C, T and G.

In the decades following the cracking of the genetic code in the 1960s – the correspondence between DNA (actually RNA) triplets and the 20 types of amino acids in biological proteins – the “one gene-one protein” mindset guided genetic research. Investigators used indirect methods to map genes to chromosomes, then painstakingly made the gene-protein assignments, describing rare, single-gene diseases one at a time.

I looked at past issues of the AJHG at decade intervals from this time of year, to place the current issue into perspective. The September 1982 journal had crude linkage maps of 4 human chromosomes, the idea of a human genome project not yet uttered. Within the next decade, a flurry of genes behind the more familiar single-gene diseases began to reveal themselves: myotonic dystrophy, cystic fibrosis, Duchenne muscular dystrophy, the first type of osteogenesis imperfecta, and the elusive Huntington disease among them.

The functioning of the human genome is much more than the protein-encoding sequences. (DOE - Genomes to Life)

The functioning of the human genome is much more than the protein-encoding sequences. (DOE - Genomes to Life)

The 2002 AJHG held the first inklings of moving beyond the single gene approach, with “genomewide” and “associations” entering the lingo, soon to be wed into the GWAS – genomewide association studies – that dominated until the recent takeover by whole exome sequencing. Articles dealt with SNPs and susceptibilities, described mutations in non-amino-acid-coding parts of genes, and included more environmentally-influenced traits and conditions, such height and bipolar disorder.

And now, the tone and content of the August 2012 issue highlight how the information in DNA goes far beyond one-gene-one-protein. Here are some such hidden meanings:

• A mutant gene behind a form of amyotrophic lateral sclerosis (ALS) also causes essential tremor. In ALS, a missense mutation, which alters an amino acid, hangs around in motor neurons and does something – we still don’t know what – that shuts down the cells. But in essential tremor, the mutation is nonsense, which halts production of the protein and activates a cellular garbage disposal pathway that removes the incomplete proteins, with less dire consequences. (The gene, FUS, accounts for only 4% of the 10% of ALS cases that are inherited).

• A fifth form of osteogenesis imperfecta (“brittle bone disease”) stems from a mutation in the control DNA sequence that lies before the protein-encoding sequence. So instead of spelling “get ready to start,” the mutation tacks five amino acids onto the 132-amino-acid protein. The gene had eluded classic linkage studies and even the Sanger sequencing of the human genome project.

• A “potential biomarker for susceptibility to and prognosis for lung cancer” lies in having 4 copies of a particular repeated sequence, compared to having 2 or 3 copies, in the promoter control region of a gene called MAPKAPK2.

• Don’t forget chromosomes! We each have TWO copies of the genome in all cells but our sperm and eggs. If a person has two recessive mutations in a disease-causing gene, it can mean either of two things: sickness if the glitches are on different copies of the same chromosomes (the “trans” configuration, inherited from both parents), yet not if the mutations are within the same gene on the same chromosome (the “cis” configuration, inherited from one parent). Geneticists have long deduced cis and trans “phase” effects in large families, but the task toughens for today’s multiplex genotyping of many thousands of individuals. Existing statistical methods infer neighboring sequences from what’s most common, constructing a “haplotype” of gene variants linked closely along a chromosome – but David Reich’s group from the Broad Institute describe a powerful new method in the August AJHG that doesn’t infer from what’s already known.

I pay special attention to the tables of contents of genetics journals because, since 1993, I’ve been the author of a human genetics textbook. The above four phenomena aren’t new – just illuminated since the genome project revealed the protein-encoding sequences, the tiny 2% that is the exome. But what may change in the next edition of my textbook is not what to include, but what, or rather who, to exclude: the “father” of genetics – Gregor Mendel.

A listserv for biology instructors recently debated Mendel’s fate, inspired by an article by Rosemary Redford of the University of British Columbia, ‘Why do we have to learn this stuff?’-A New Genetics For 20th Century Students. In this day when people can order DNA tests over the Internet, some said, the famed pea plant experiments published in 1865 are no longer relevant, or even interesting. Others objected to the folklore of Mendel as genetics’ Galileo, the misunderstood hero working tirelessly in his monastery garden, then his work ignored.

And so the story of the monk and the beautiful illustrations of the tall and short pea plants with their wrinkled and round, green and yellow peas that have festooned chapter 4 in my textbook for 10 editions will probably be buried in an appendix in the 11th. For in this post-genomic age, there’s simply too much else to discover, in both the obvious and not-so-obvious terrain of our genomes. The same can be said for all of science – whenever we take a huge leap, such as sequencing the human genome, what we discover is that we actually have much more to learn.

Ricki Lewis About the Author: Ricki Lewis received her PhD in genetics from Indiana University. Her ninth book, The Forever Fix: Gene Therapy and the Boy Who Saved It, narrative nonfiction, was just published by St. Martin’s Press. Most of her other books are college life science textbooks, including "Human Genetics: Concepts and Applications," (10th edition, 2012) from McGraw-Hill Higher Education. Routledge Press published "Human Genetics: The Basics" in 2010. Ricki has published thousands of magazine articles, from Discover to Playgirl, but mostly in The Scientist. She is a genetic counselor at CareNet Medical Group in Schenectady, NY and teaches "Genethics" online for the Alden March Bioethics Institute of Albany Medical College. Ricki is a hospice volunteer and a frequent public speaker (Macmillan Speaker’s Bureau). Ricki’s blog Genetic Linkage is at www.rickilewis.com and she tweets at @rickilewis. Follow on Twitter @rickilewis.

The views expressed are those of the author and are not necessarily those of Scientific American.






Comments 11 Comments

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  1. 1. john mcdonald 4:50 pm 08/20/2012

    Speaking as a Biology teacher of many years, the effort to ignore Mendel is to lose one of the best teachable stories in science. The introduction to genetics by way of Mendel is a seminal event for many students who otherwise might be indifferent to 19th century science discovery.

    Similarly the work of Pasteur inspires many to consider microbiology as a career.

    Everyone seems to forget that the class facing you brings diverse backgrounds, from practically third world mind sets to the most advanced skills. A teachers job is to bring all into a modern outlook, the DNA must wait for its own moment.

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  2. 2. blindboy 6:34 pm 08/20/2012

    Isn’t there a statistical suspicion over Mendel’s work? To the effect that he indulged in that favourite sport of scientists, confirmation bias.

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  3. 3. Bijoou 10:46 pm 08/20/2012

    Loved the essay. Carried me back to the hangar-size, 300 seat, undergrad biology lecture hall in 1966 where I fell in Love w/DNA. ”
    Our professor had just about finished outlining what then known about the makeup of the human cell. Pointing to a spot in a large, colorful banner diagram covering the white board he said, “Now this is something called a mitochondria. And we have no idea exactly what it does. Could even be a piece of left over useless junk.”
    Sometimes we need remindi

    Link to this
  4. 4. Bijoou 10:47 pm 08/20/2012

    Loved the essay. Carried me back to the hangar-size, 300 seat, undergrad biology lecture hall in 1966 where I fell in Love w/DNA. ”
    Our professor had just about finished outlining what then known about the makeup of the human cell. Pointing to a spot in a large, colorful banner diagram covering the white board he said, “Now this is something called a mitochondria. And we have no idea exactly what it is or what it does. Could even be a piece of left over useless junk.”

    Sometimes we need remindi

    Link to this
  5. 5. rickilewis 11:03 pm 08/20/2012

    Hi, John. I could never totally ignore Mendel. His insights are timeless and the experiments, whether or not he fudged the numbers a little, brilliant. But I can cut back on the biographical info and find a way to illustrate the experiments in a briefer way. One of the challenges in textbook writing is to embrace the new without adding too many pages. Another challenge is satisfying all of the instructors who review each edition. I’ve got about a year to think it over. Thanks for commenting.

    Link to this
  6. 6. BigInScience 6:07 am 08/21/2012

    I enjoyed your essay Ricki! My upcoming book “Rush: Science and Technology in Our Acceleration Age” discusses accelerating trends in science and technology and the implications of these trends. One of my favorite sections of the book is the rapidly decreasing cost of sequencing the human genome (you can view the book at BigInScience.com).

    I’ve read elsewhere similar concerns over the relevance of Mendel. Some have noted that diseases like Cystic Fibrosis, once believed to be inherited in a classical recessive Mendellian pattern (ie where the “dominant” allele coding for a normal CFTR masks the expression of a recessive mutated CFTR), actually manifests with mild symptoms in “carriers” or those carrying the recessive allele (ie individuals carrying a single recessive allele are at increased risk for sinusitis).

    Do you believe Mendel is still relevant?

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  7. 7. rickilewis 7:20 am 08/21/2012

    Intermediate phenotypes in heterozygotes have always been a possibility. It depends on the nature of the phenotype. In Tay-Sachs disease, for example, the enzyme deficiency has a threshold effect, so that heterozygotes do not manifest symptoms. But if you define phenotype as enzyme level, yup, they’re not normal. Sickle cell carriers are at higher risk for respiratory complications in low oxygen situations. This effect is not seen, however, in Huntington disease, where a deletion has no effect. That is because this is a triplet repeat, gain-of-function mutation. So recessive/dominant has never really been a black/white issue. One of the chapters in my textbook, which I’ve called “Beyond Mendel’s Laws,” discusses the various seeming exceptions.

    To answer your question, yes, Mendel is still and always will be relevant — I just have to shorten the coverage. This is a good example of why a science textbook needs to be revised fairly often. I’ve been writing textbooks a long time, and I do not recall a two-year period when so much has changed in genetics. Thanks for commenting and good luck with your book!

    I will check out your books. Kevin Davies’ “The $1,000 Genome” from 2 years ago is excellent.

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  8. 8. Bill_Crofut 10:59 am 08/21/2012

    The information on the effects of mutations presented in the August 2012 issue of the American Journal of Human Genetics would seem to have been recognized by a French zoologist over 3 decades ago:

    A mutation substituting one or more amino acids for one or more others in the globin of human hemoglobin may, depending on its location, have serious effects on the structure (at various levels) and properties of this pigment; such as the case of abnormal hemoglobin S in the anemia of cresentic red blood cells (drepanocytosis or sickle cell anemia). The molecules of this hemoglobin line up in filaments and form stiff rods, grouped into bunches which distort the blood cell. The red blood cells containing hemoglobin S are practically destroyed, and the resulting anemia causes serious troubles—such as the increase of the bone marrow which, in order to speed up the genesis of red blood cells, modifies the skull bones; the hypertrophy of the heart; and the accumulation of crescentic blood cells in the spleen, which increases in size and becomes fibrous.

    The pleiotropic mutation, from what we now know about it, causes the loss of one enzyme, which results in a number of consequences (such as the eye pigment of Drosophila, the synthetic ability of the fungus Nejurospora). This mutation does not construct anything; it alters or destroys preexisting elements.
    [Prof. Pierre-P. Grassé. 1977. EVOLUTION OF LIVING ORGANISMS: Evidence for a New Theory of Transformation. New York: ACADEMIC PRESS, p. 56]

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  9. 9. BigInScience 1:31 pm 08/21/2012

    Thanks Ricki. I can only imagine how rapidly your field is progressing. I look forward to reading your textbook and checking out Kevin Davies’ book.

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  10. 10. rickilewis 5:31 pm 08/21/2012

    Thanks, Bill, excellent reference. I always wondered why different mutations in the beta globin gene are different clinical entities, yet different mutations in the CF gene are variants of CF. Very inconsistent, but maybe the reason is historical. Does anyone know?

    To get around the high cost of textbooks (I hope my editors don’t read this!) I wrote a short and very cheap intro human genetics book called Human Genetics: The Basics. The same info as a textbook, but accessible, with lots of stories and cases, but no pretty pictures. If you are interested be sure not to click on the hardcover. And my narrative nonfiction (my baby) “The Forever Fix: Gene Therapy and the Boy Who Saved It” will be out in paperback in January. (End of shameless book plugs but I don’t get paid for blogging so I guess it is ok.)

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  11. 11. Mong H Tan, PhD 6:31 pm 08/26/2012

    RE: Nothing! — As any insightful Genetics textbook authors and/or geneticists shall maintain their professionalism and truth; especially truth to the scientific progress and history of our human endeavors (since the Enlightenment) in the STEM pedagogy, including our Biomedicine and Humanity, today and beyond!?

    Briefly, No one shall erase nor replace Gregor Mendel (1822-84) from the history of his scientific and crucial discovery of, and experimental works on, the Science or the organic mechanisms of heredity in peas plants, a specialized field that is commonly known as Genetics today and beyond!

    Furthermore, Mendel’s original works (1856-63) were scientifically sound, solid, and foundational: as analyzed from the perspective of our Modern or Developmental Biology, Biomedicine, and Genomics today, an increasingly specialized and foundational field that has had since the 1980s been expanded, extended, and delineated from the neo-Darwinist pseudoscientific rhetoric, or the reductionist sophist dogma of “evolutionary biology” as dictated by the Modern Synthesis (since 1940s); or the mostly unscientific nor critical Gross Superimposition of the naturalist Charles Darwin’s (1809-82) “natural selectionist theory of Evolution” (1859) — over — the Mendelian “developmental theory of Genetics” (1866) by the all too over-zealous, neo-Darwinists, reductionists, and sophists alike, in our Modern Biology and Humanity today, especially since the rediscovery of Mendel’s seminal works, at the turn of the 20th century!?

    Since 2009, especially after much celebration and reflection on Darwin’s 200th birthday and on his voluminous naturalist works, I have had begun to warn and refute the generations of neo-Darwinists, reductionists, sophists biased tendency to dictate and corrupt all fields of Biology and Humanity by their 1940s-synthesized, pseudoscientific “evolutionary rhetoric” including their current attempts to corrupt our Biomedicine and Psychiatry that I recently observed here — http://www.sciencebasedmedicine.org/index.php/21546/#comment-96992 — “Do We Need “Evolutionary Medicine”? — RE: Science-based Medicine vs Evolutionary (neo-Darwinist) Medicine!?” (SciencebasedMedicineUSA; August 4, 2012).

    Best wishes, Mong 8/26/12usct5:31p; practical science-philosophy critic; author “Decoding Scientism” and “Consciousness & the Subconscious” (works in progress since July 2007), “Gods, Genes, Conscience” (iUniverse; 2006 — http://bookstore.iuniverse.com/Products/SKU-000034974/GODS-GENES-CONSCIENCE.aspx ) and “Gods, Genes, Conscience: Global Dialogues Now” (blogging avidly since 2006 — http://www2.blogger.com/profile/18303146609950569778 ).

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