Attendees at last year's annual meeting of the American Society ofHuman Genetics in San Francisco heard or saw 2,016 oralpresentations and posters. One of them bore the heading: "Is there amaternal effect in multiple sclerosis?"
That same report, updated, appears in the current issue of TheLancet, dated June 22, titled: "Evidence for genetic basis of multiplesclerosis." Its principal author is medical geneticist Dessa Sadovnik,at the University of British Columbia in Vancouver. Her brief articlelists 30 footnoted journal references.
Last year, according to the Science Citation Index, 3,394 journalspublished 75,656 papers concerning all the fields of genetics. Thosethousands are all clones of a single founder article printed 130 yearsago in an obscure European journal, Transactions of the NaturalScience Society of Brunn, Bohemia.
Its title: "Experiments with plant hybrids;" its author, Gregor Mendel,a monk and botanist at the Augustinian monastery of Brunn (nowBrno, in the Czech Republic).
Every geneticist alive today cuts his or her teeth on the story of howGregor Mendel discovered the laws of inheritance by cross-breedingordinary garden peas. From the variegated colors, sizes, shapes andother traits of the stalks, leaves and seeds, he construed the simplestatistical odds by which male and female plants passed on theircharacteristics to subsequent pea generations.
Thus, immediate progeny stood a 50-50 chance of inheriting a traitfrom either parent; their offspring, 25-50-25, and so on.
From this scenario it was just a conceptual leap to the notion ofgenes, as the conveyors of inheritance.
That's more or less where things stand today in discerning theinheritance of multiple sclerosis (MS). This genetic black box still isstubbornly shut by several locks:
* How much of MS is inherited altogether, and how much isenvironmental?
* Is the disease due to one gene or several?
* On which human chromosome or chromosomes do the genesreside?
* How are these inheritance factors passed on from parents tooffspring?
One school of current scientific opinion speculates that maternalinfluences, genetic or environmental, ranging from aberrantmitochondria (which are inherited solely from the mother) to adverseconditions in utero, during pregnancy and delivery to breast feedingmay be at the non-genetic root of MS causation.
Sadovnik and her co-workers at Canada's 14 regional MS clinics setout to test this maternal hypothesis by applying the statistics ofpopulation genetics _ essentially as Mendel had done to his peaplants.
They knew that twice as many women as men contract this complexdisease; that it's onset ranges from 10 to 59 years of age, with mostcases diagnosed between 20 and 40; that it results from anautoimmune reaction against central nervous system antigens; that ifone of a pair of identical twins has MS, the other is 300 times morelikely than the general population to incur the disease. This worksout, paradoxically, to only a 30 percent risk. Genetic inheritancewould expect 100 percent concordance between identical twins,Sadovnik pointed out.
Half-Sibs Stand In for Scarce Twins
Twin pairs are favorite in vivo models of human genetic research,because one acts as a genetic and environmental control for the other.But Sadovnik realized that it would take an almost astronomicalnumber of such siblings, identical and fraternal, to unmask the truenature vs. nurture genetics of MS.
Instead, she and her co-authors turned to half-siblings _ half-brothersand half-sisters _ who share only one biological parent in common.Thus, they are only half as likely as full siblings to have inheritedwhatever causes MS. "Half-sibs," Sadovnik pointed out, "share 25percent of their genetic material, whereas full-sibs share 50 percent."
Their study reported in The Lancet interviewed 16,000 MS patientsacross Canada, from Newfoundland to British Columbia, anddeveloped full data on sibling and half-sibling members of theirfamilies.
Of the 16,000 patients polled, 939 had both 1,395 full sibs and 1,839half-sibs. Of the former, 35 had MS; of the latter, 18.
"The significance of the half-sib cohort," Sadovnik told BioWorldToday, "is the fact that we can measure factors such as shared familyenvironment. Our study surveyed half-sibs who live together, half-sibs who have never met; half-sibs who were raised apart."
"A study of identical twins separated early in life and raised apart,"the Lancet paper said, "would help differentiate the role of genes andenvironment, but such twins are too rare for this approach to befeasible in MS (or any other autoimmune disease.)"
"This particular paper," Sadovnik observed, "very clearly showedthat the well-known increased frequency of MS among familymembers is due to the common genetic material they share, not theircommon family environment.
"We found no evidence," she reported, "to support the notion thatthere are maternal factors or any other common familial non-geneticfactors influencing risks.
"Our results," her paper concludes, "support the interpretation thatthe difference between sibling and half-sib risk is entirely attributableto genes. Halving the number of potentially contributory genes [bycomparing full-sib and half-sib rates] lowers the risk of MS by afactor suggestive of more than one gene."
"These findings," she observed, represent "the first reallyunambiguous information that the excess of MS within families isstrictly genetic. And of course, this has large implications forbiotechnology."
Sadovnik and her co-authors now are in hot pursuit of the elusive MSgene or genes. "We're already working on genome screening," shesaid, "trying to identify potential hot spots for candidate MSsusceptibility genes. We're not focusing on any one chromosome inparticular, but looking at the entire genome.
"While we're saying that there are no environmental risk factorsincreased in families," Sadovnik continued, "we do know that thereseem to be some non-genetic factors as well in the generalpopulation." Hunting those down is on a parallel track of herconsortium's research planning.
In determining if a patient has MS, a physician applies the PoserDiagnostic Criteria, developed by clinical neurologist Charles Poser.He practices at Boston's Beth Israel Hospital, with a research focuson MS pathogenesis and epidemiology.
"Sadovnik's paper," Poser told BioWorld Today, "is a very key,landmark study, because of the continued controversy about the roleof the environment in MS etiology." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.