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Copyright O 1997 by The Johns Hopkins University School of Hygiene and Public Health
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Vol. 19, Mo. 1
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Evolving Methods in Genetic Epidemiology. IV. Approaches to NonMendelian Inheritance
Stephanie L. Sherman
INTRODUCTION
Subsequently, a review of the analytic approaches that
have been used or proposed to identify such traits will
be presented.
Over the years, genetic epidemiologists have identified traits that are due to the effect of a single gene,
but one that does not follow the rules of Mendelian
inheritance. Such anomalies in inheritance patterns
were sometimes attributed to ascertainment biases or
the interaction between environmental and/or other
genetic influences. Recent advances in molecular genetics in humans and experimental animals, however,
have provided evidence to show that single genes
themselves can have attributes that result in a nonMendelian pattern of inheritance of the expressed trait.
Three phenomena of genes that lead to such patterns
will be reviewed below; two patterns result from mutations that alter a normal state (one due to a mutation
that causes a stable trinucleotide repeated sequence to
become unstable and the other due to some mechanism
that alters the effect of genomic imprinting) and the
other pattern results from a gene belonging to the
mitochondrial genome, not the nuclear genome. Table
1 describes some of the resulting features of each of
these attributes.
So-called "complex traits" are also defined in the
literature as non-Mendelian traits. These are usually
attributed to complex interactions between more than
one genetic and/or environmental factor, not to attributes of a single gene. For purposes of this review,
the narrow definition of non-Mendelian inheritance
due to properties of a single gene will be used.
The analytic approaches used to identify such patterns fall into two general categories: 1) basic statistical and epidemiologic approaches used to detect differences among groups and 2) genetic model fitting. In
the following section, the underlying biology of each
of the attributes and resulting consequences with respect to the expression of the trait will be described.
BIOLOGIC BASIS AND CONSEQUENCES
Dynamic trinucleotide repeat sequence mutation
"Anticipation" is the primary characteristic of a
dynamic trinucleotide repeat sequence mutation, and
is defined as the occurrence of an inherited trait that
progressively increases in severity in successive generations. Measures of severity include recurrence risk,
symptoms, or age-of-onset. Myotonic dystrophy has
been the classic example of a trait which shows anticipation (for a review, see Harper et al. (1)). For this
autosomal dominant disorder, an increase in the severity of symptoms and a decrease in the age-of-onset is
observed over generations: Family members in the
older generations may exhibit only cataracts late in
life. In succeeding generations, affected members have
typical neuromuscular features, myotonia and dystrophic changes, with onset usually in adolescence or
early adult life. Finally, there is a congenital form with
severe neuromuscular problems.
Although this pattern of anticipation was recognized
by Fleischer (2) (an ophthalmologist) and later quantitatively analyzed by Bell (3), it was thought to be a
statistical artifact for over 40 years. Penrose (4), in
1948, attributed this pattern to selection biases resulting from preferential ascertainment of three groups: 1)
parents with a late age-of-onset, as an earlier onset
would limit their ability to reproduce, 2) the childhood
generation with early onset because of the severity of
the disorder, and 3) parent-offspring pairs with simultaneous onset, as most studies are conducted over a
short time period. Penrose's overall conclusion was
that "anticipation" was indeed apparent, but not due to
a biologic phenomenon. Harper et al. (1) present a
fascinating historical perspective of this conclusion
and why it had such a strong influence. They remark
that, since the time of Penrose's (4) paper until the
early 1980s, geneticists have "almost unanimously
dismissed anticipation as an artifact resulting from
December 27,1996, and accepted for publication May 27,1997.
Abbreviations: ANOVA, analysis of variance; FMR1, fragile X
syndrome gene; MANCOVA, multiple analysis of covariances;
mtDNA, mitochondrial DNA.
From the Department of Genetics, Emory University, 1462 Clifton
Road, Atlanta, GA 30322. (Reprint requests to Dr. Sherman at this
address.)
44
Non-Mendelian Inheritance
45
TABLE 1. Features of inheritance patterns caused by repeat sequence mutations, mutations In genomic imprinting, and
mitochondria! mutations
Feature of
disorder
Repeat sequence
mutation
Qenomtc
ImprintfriQ,
Mtochondrtal
mutation
Intergeneration effects
Primary feature: arrttclpatton
No anticipation—but differences
observed among generations
Possible anticipation observed
over one or two generations
(heteroplasmy-»nomoplasmy)
Parentof-origin effects
Yes—parental effects differ
for each disorder
Primary feature: parental effects
differ for each disorder
Yes—always female effect
Transmission
Mendelian
Mendelian
Primary feature: only maternal
transmission, no paternal
transmission
Sex ratio of affected
individuals (malerfemale)
1:1 (unless X-Unked)
1:1 (unless X-llnked)
1:1
Sex ratio among carrier
parents (male:female)
Complex
1:0 or 0:1
0:1
observational biases" (1, p. 13). They also point out
that clinicians, on the other hand, have insisted that
anticipation was real, not just apparent, in myotonic
dystrophy, although they accepted that the "geneticist
should know best about behavior of genes" (1, p. 13).
In 1984, a similar pattern of anticipation was observed for the fragile X syndrome, an inherited form of
nonspecific X-linked mental retardation (5, 6). However, in this case there was not an increase in severity
of the trait; instead, there was an increased risk for an
offspring of an obligate carrier to exhibit the syndrome. Various complex genetic models were proposed to explain this pattern (e.g., see Israel (7) and
Laird (8)) as well as ascertainment biases. It was not
until 1991, when the gene responsible for the syndrome (FMR1) was isolated, that a biologic explanation was identified (9-12). Individuals can be characterized as 1) noncarriers, 2) carriers with no
symptoms, or 3) carriers with the fragile X syndrome
based on the length of their FMR1 gene. This length
difference is due to the instability of a trinucleotide
repeat sequence within the FMR1 gene. Once mutated,
this sequence becomes unstable and most often expands in size when passed from parent to child, especially from mothers to their offspring. An individual
expresses the fragile X syndrome when the repeat
sequence exceeds 200 repeats. Identification of this
dynamic repeat sequence mutation led to the examination of other disorders that showed anticipation.
Myotonic dystrophy was the next disorder to be identified (13-15). The repeated sequence, and its location
within the gene, differ from that in the fragile X gene;
thus, characteristics of the expression of the trait differ. However, the main feature of anticipation remains;
with each succeeding generation, the disorder becomes more severe in members carrying the mutation,
and this severity is highly correlated with the length of
Epidemiol Rev Vol. 19, No. 1, 1997
the repeat. Subsequently, at least seven other singlegene dominant disorders have been found to be due to
mutations in a trinucleotide repeat sequence (for a
review, see Ashley and Warren (16)). Each disorder is
unique due to the position of the repeat sequence in the
gene, the trinucleotide sequence itself, the function of
the gene, and the parent-of-origin effects on the rate
and size of expansion to the next generation. Irrespective, each disorder shows the general phenomenon of
anticipation.
Genomic imprinting
Genomic imprinting refers to an epigenetic effect
(i.e., a nonheritable effect) that causes differential expression of a gene depending on the sex of the transmitting parent (for a review, see Cassidy (17) and
Langlois et al. (18)). Such effects are functional
changes, not permanent changes, that occur through
the modification of DNA or chromatin structure, although the details of the process are unknown. The
imprinting process dictates the expression of a gene
from only one parent of a certain sex rather than both
genes of an homologous pair. Imprinting is a normal
developmental process that regulates gene expression
and is thought to affect only a relatively small number
of genes. Research shows that the process leading to
the imprint must have the following characteristics: 1)
it is reversible through generations, 2) it leads to
expression or repression of a gene, 3) the epigenetic
factor is erased and reestablished according to the sex
of the parent during gametogenesis, and 4) the imprint
is faithfully maintained after DNA replication and
thereby remains fixed through development and the
lifetime of the individual.
The first human disorder recognized to be the
consequence of the alternation of genomic imprint-
46
Sherman
ing was the Prader-Willi syndrome (19, 20). This is
a complex multisystem disorder, including infantile
hypotonia, hypogonadism, developmental delay/
mild mental retardation, hyperphagia leading to
obesity, short stature, and dysmorphic features (21).
It is now known that the Prader-Willi syndrome is
caused by any mechanism that leads to the loss of
the paternal contribution of a gene(s) in the chromosome region of 15ql 1—13. A completely different syndrome, the Angelman syndrome, occurs
when the maternal genetic contribution is lost in this
chromosome region (22). The Angelman syndrome
is characterized by severe mental retardation,
ataxia, seizures, unprovoked bursts of laughter, and
dysmorphic features unlike those of the PraderWilli syndrome (23). Thus, in this chromosomal
region genes are normally expressed only in a single
dose, and such expression is regulated by imprinting. When the genetic contribution from one parent
is missing, the balance of expression is disrupted.
Recent research has shown that the genes contributing to the Prader-Willi and Angelman syndromes
are different, but probably adjacent (24).
Loss of the specific genetic material from a parent
can result from deletions or uniparental disomy. Uniparental disomy occurs when both members of a chromosome pair in an offspring are inherited from only
one parent. This is a sporadic event that sometimes
results from abnormal segregation of a chromosome
pair during meiosis. Alterations in imprinting can result also from specific mutations in regulatory sequences of a gene. Deletions and mutations in the
imprinting process can lead to recurrent cases in families.
Genomic imprinting is critical for normal development; when disrupted, human disorders result. A clear
understanding of its function in normal development is
unknown, although it does seem that some imprinted
genes are important in growth. Molecular studies of
cancers provide such evidence. Some cancers, including Wilms' tumor and retinoblastoma/osteosarcoma,
show genetic alteration of the paternally-derived chromosome (for a review, see Sapienza and Hall (25)). It
may be that the paternal allele of a tumor suppressor
gene is normally inactive due to genomic imprinting.
Loss of a maternal active allele may lead to abnormal
cell growth and eventually to cancer.
The mechanisms leading to imprinting, and ways to
disrupt those processes, are active areas of research.
Inevitably, alterations in imprinting will be found to be
important in other complex phenotypes and/or imprinted genes will be found to modify phenotypes of
single- or multigene disorders.
Mitochondrial genome
As reviewed by Grossman (26), the field of mitochondrial genetics has gone through three significant
advances: The first advance was the discovery that
mitochondria are essential for energy production in the
cell; they are the "power plant" for eukaryotic cells.
The second advance was the finding that mitochondria
contain their own genome; each contains multiple
copies (two to 10 copies) of a 16,569 base-pair circular
DNA duplex. The 13 polypeptides encoded by the
mitochondrial DNA (mtDNA) are all subunits of enzyme complexes involved in energy production. The
other subunits (over 60) involved in this system are
coded in the nuclear genome. The third, and most
recent, advance is that mutations in the mtDNA lead to
a number of genetic disorders. The full range of diseases that have a mitochondrial component is unknown but clearly involve rare disorders, such as
Leber's hereditary optic neuropathy, and common disorders, including types of epilepsy and cardiomyopathy (for a review, see Schoffner and Wallace (27) and
Wallace (28)). Disorders resulting from mitochondrial
mutations are expected to involve multiple systems
due to the key function of mitochondria, energy production. Depending on the type and function of the
cell, the number of mitochondria per cell ranges from
hundreds to thousands. As a consequence, the relation
between phenotype and genotype is complex. Many
times, there is extreme variation in the phenotype of
known mitochondrial mutations. This may be due to
intrinsic properties of the mitochondria and/or to genegene or gene-environment interactions.
It is important to describe the features of mitochondrial genetics to understand the possible phenotypic
outcomes. First, mtDNA is located in the cytoplasm.
Only the cytoplasm from the egg is transmitted to the
zygote, sperm rarely contribute mtDNA to the zygote.
Thus, mothers and all their offspring share the same
mtDNA. Second, there are thousands of mtDNA molecules per cell. Unlike nuclear DNA, mtDNA is randomly distributed to daughter cells (termed replicative
segregation). If mutant mtDNA is present among normal mtDNA (a mixture of mutant and normal mtDNA
referred to as heteroplasmy), the proportion of mutant
to normal mtDNA can change after one cell division.
Any two offspring are likely to receive different proportions of mutant mtDNA from a mother who is
heteroplasmic. The resulting mtDNA of an offspring
can be of essentially three states: a mixture of nonnal
and mutant mtDNA (heteroplasmy), purely normal
mtDNA, or purely mutant mtDNA (homoplasmy).
This phenomenon potentially causes the phenotype
observed among offspring to be variable.
Epidemiol Rev Vol. 19, No. 1, 1997
Non-Mendelian Inheritance
There are also tissue-specific effects. These result
from different proportions of mutant mtDNA in each
cell lineage and also from different energy needs of
each tissue. Thus, a specific mtDNA mutation may be
expressed in different phenotypic forms in different
individuals within the same pedigree. Categorizing
individuals within a pedigree as "affected" may be
problematic as they may have vastly different phenotypes.
One feature that may reduce some of the variation
relates to the threshold effect. A significant decrease in
energy production per mitochondrion does not occur
until the proportion of mutant mtDNA is high, suggesting a threshold effect. This effect may reduce the
potential variation in the phenotype expected from the
continuous distribution of the proportion of mutant
mtDNA.
Lastly, mutations in mtDNA occur at rates 10-20
times higher than in nuclear DNA, and those mutations quickly become fixed within a few generations.
As a consequence, pedigrees showing recent mtDNA
mutations may occur relatively frequently. Heteroplasmy is most often observed in individuals in the
older generations where the initial mutation occurs.
All the described features of mitochondrial genes inevitably lead to a complex phenotype within families
when a mutation occurs. Additionally, there is known
interaction between the nuclear and mitochondrial genes.
Thus, it may be that many complex traits will result from
an effect of the variation in mitochondrial genes.
ANALYTIC APPROACHES TO IDENTIFY NONMENDELIAN TRAITS
Specific analytic methods to investigate involvement of the three attributes of single genes leading to
non-Mendelian inheritance have lagged behind those
to identify single-gene Mendelian traits. This is not
surprising, as the biologic causes of these patterns
have been only recently understood. Issues concerning
possible ascertainment biases that lead to nonMendelian patterns have been well defined and must
be considered when examining any trait. Furthermore,
traits due to X-linked genes and due to the vertical
transmission of infectious agents may also show similar inheritance patterns as the ones discussed. Thus,
uncovering evidence for specific biologic causes is a
difficult task. Table 1 outlines the features of each type
of mutation that need to be considered when hypothesizing non-Mendelian inheritance of a trait. As there
is overlap of features, it may be possible only to
narrow down possible alternatives. Although methods
to identify each primary feature will be discussed
separately, all aspects of the family data must be
examined and evidence put together as a puzzle.
Epidemiol Rev Vol. 19, No. 1, 1997
47
There are two general types of questions that can be
asked concerning the involvement of the above properties. Perhaps the simplest is "Can one of these phenomena be me primary cause of the observed inheritance pattern?". This was the question asked for
myotonic dystrophy. The more difficult question to
ask is "if one of the components of a complex trait
involves one of the three phenomena." For example,
this question has been asked for bipolar affective disorder, which shows excess, but not exclusive, maternal
inheritance.
Correcting for ascertainment
Before any analytic approach is taken to examine
inheritance patterns, the scheme used to ascertain family data must be defined and a method to correct
for that scheme implemented. If left uncorrected, resulting biases can mimic some of the features of nonMendelian inheritance. Ottman et al. (29) provide an
example from their study of the inheritance of epilepsy. One approach to ascertain probands and their
offspring was examination of medical records. Histories of epilepsy in mothers are routinely included in
obstetric records, while those of fathers are not. Thus,
this approach may lead to better ascertainment of
offspring of affected mothers than of affected fathers
resulting in a sample that looked like excess maternal
inheritance.
There are various ways to correct for ascertainment
if there is a clear understanding of all potential biases.
This is a feat in itself. A typical way to identify
possible problems of ascertainment in family data is to
test for homogeneity among sibships, ascertained in
different ways but predicted to provide similar estimates of segregation parameters. An outline of methods to correct for ascertainment is beyond the scope of
this review and, therefore, will be mentioned here only
to warn the reader that correction must be done prior
to any of the applied methods described below.
Identifying group differences
Intergenerational effects: anticipation. Anticipation leads to intergenerational effects of a particular
pattern: the older generation shows less severe expression of a disorder than the subsequent generation.
Many dynamic repeat sequence mutation disorders,
and some disorders with mitochondrial mutations,
show such effects. For mitochondrial mutations, anticipation usually is observed in the early generations
after the initial mutation; the original mutation is
present in a heteroplasmic state and quickly becomes
fixed to a homoplastic state.
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Sherman
Examination of the correlation of age-of-onset or
severity parameters between affected parent-offspring
pairs and among affected sibs is an initial screen for
anticipation. There should be a smaller correlation
among parent-offspring pairs compared with sib pairs.
Bell (3) clearly identified this pattern for myotonic
dystrophy.
Mclnnis et al. (30) examined anticipation in bipolar
affective disorder. As an initial screen, they used lifetable analysis and Gehan's generalized Wilcoxon test
to look at differences in parameters of severity between generations. They also used the Cox proportional hazards model to analyze relationships between
generations and onset of disease while controlling for
an effect of birth cohort, an obvious variable that may
lead to spurious conclusions. Using these intergenerational comparisons, they found both an earlier age-ofonset and an increased disease severity in subsequent
generations.
Anticipation also may be observed as an increase in
recurrence risk with each generation, instead of an
increase in disease severity. This pattern was observed
for the fragile X syndrome, and was revealed by
examination of segregation ratios in each generation
using both classic and complex segregation analyses
(5, 6). A segregation ratio is defined as the proportion
of affected offspring among the total number of offspring in a sibship. Briefly, the trait was assumed to be
due to a single X-linked gene, and the penetrance (i.e.,
the probability of expressing the disorder given the
abnormal genotype) was compared among the different sibships according to their position in the extended
pedigree and according to phenotype of the mother
(i.e., affected mother versus unaffected mother). Penetrance assuming an X-linked genetic model (which
equals twice the segregation ratio) was estimated using
maximum likelihood methods, and comparison of estimates for different types of sibships was done using
tests of homogeneity. Significant heterogeneity was
found; penetrance was significantly lower in sibships
found in older generations compared with those in
younger generations. Thus, traditional methods of segregation analysis were used to identify anticipation.
Parent-of-origin and transmission effects. Parentof-origin effects result from all three phenomena; thus,
this feature must be observed in concert with others to
conclude one or the other phenomena. Parent-of-origin
effects are the sine qua non of genomic imprinting.
Imprinting is an epigenetic attribute of a gene—the
imprinted gene itself is transmitted in a Mendelian
fashion. The parent-of-origin effect seen among many,
but not all, of the repeat sequence mutations behaves
like an imprint, although die biologic cause of this
effect is unknown. For example, for the fragile X
syndrome and myotonic dystrophy, the risk to expand,
and the size of that expansion, is much larger when the
mutation is transmitted from the mother compared
with that from the father. For Huntington disease, the
opposite is true. Thus, die risk and size of expansion or
contraction of die repeat sequence differs when transmitted from one parental sex versus the other. Again,
this is an epigenetic effect, the mutated gene itself is
transmitted in a Mendelian fashion. For mitochondrial
mutations, the parent-of-origin effect results from
transmission dirough ova, not through sperm. Thus,
the transmission of the disorder can be examined together with parental effects to distinguish mitochondrial mutations from repeat sequence mutations and
imprinting.
The overall methodological approach is to compare
the difference in penetrance or expression of the disorder in offspring of an affected mother versus an
affected father. Ottman et al. (29) examined parental
effects for epilepsy. Cumulative incidences of unprovoked seizures to age 25 years were 8.7 percent and
2.4 percent in offspring of affected mothers and affected fathers, respectively. Using Cox proportional
hazards analysis to calculate rate ratios for seizures in
offspring, they found mat the sex of the affected parent
was significant, not the etiology of the parent's seizures. These results suggest a maternally transmitted
influence on seizure susceptibility. Mili et al. (31)
extended the approach used by Ottman et al. (29) to
include other members in the pedigree, namely offspring of probands' sibs and offspring of probands'
first cousins. McMahon et al. (32) examined parental
effects on bipolar affective disorder. They compared
frequencies and life-time risks of disease among offspring of transmitting mothers and fathers and among
maternal versus paternal relatives of probands and
found evidence for a maternal effect in transmission.
Lichter et al. (33) took a similar approach to look for
gender-related differences in expression of the
Tourette syndrome. Univariate tests including analysis
of variance (ANOVA) and Mann-Whitney statistic
were used first to compare clinical profiles of subjects
with maternal versus paternal inheritance of the
Tourette syndrome. They also used principal component analysis to reduce the measures to summary variables, and dien used multiple analysis of covariances
(MANCOVA) to compare maternal versus paternal
inheritance groups on factor scores. They found that
maternal transmission of the Tourette syndrome was
associated with a different set of clinical variables
compared with paternal transmission, consistent with
genomic imprinting of the Tourette syndrome.
Sun et al. (Emory University, Atlanta, Georgia, unpublished manuscript) described two statistical tests to
Epidemiol Rev Vol. 19, No. 1, 1997
Non-Mendelian Inheritance
screen for involvement of mitochondrial mutations in
a complex trait using properties of maternal transmission. They examined aspects of a one-sample and
two-sample test using different types of relative pairs.
The one-sample test compared the observed risk of a
proband's relative with the maximum risk, assuming
no involvement of mitochondrial mutations. If the
observed risk is higher than expected under the null
hypothesis, a mitochondrial mutation is implicated.
The two-sample test compared the risk of proband
relatives along the matrilineal line with those along the
nonmatrilineal line. If mitochondrial mutations are
involved, the risk would be higher among matrilineal
relatives. The power of these tests was studied under a
variety of inheritance models involving both nuclear
and mitochondrial mutations.
Other characteristics of disease patterns. Other
characteristics of a disorder can be used to distinguish
the possible attributes of single genes from other complex genetic models, including the sex ratio among
affected individuals and among carrier parents (table
1). In this section, to lay the groundwork, several
examples of approaches to distinguish models will be
presented.
A complex model to explain parent-of-origin differences is the sex-specific threshold model. It is assumed that genetic and/or environmental factors lead
to sex-specific liability thresholds that cause one sex to
be more susceptible to a disorder than another (e.g.,
model assumed for pyloric stenosis). If it is assumed
that females have the higher liability or threshold, two
predictions result. First, the risk among offspring of
affected females will be higher than that for affected
males. This observation would be identified by any
test of group differences or segregation ratio differences as described above. Second, the disorder will be
more frequent among males than among females in the
general population and in offspring of affected parents. This observation would be inconsistent with, say,
mitochondrial mutations. Thus, examination of population parameters, as well as inheritance parameters,
provides support for one model over another.
Inheritance patterns due to X-linked mutations may
lead to excess maternal inheritance. Examination of
the sex-specific parent-offspring pairs can distinguish
rare X-linked mutations from mitochondrial mutations. X-linked recessive inheritance predicts a higher
risk in sons of affected females compared with sons of
affected males, and equal risks for daughters of affected females and of affected males. Therefore, excess maternal inheritance is restricted to sons of affected females. X-linked dominant inheritance
predicts a higher risk in sons of affected females
compared with those of affected males. However, a
Epidemiol Rev Vol. 19, No. 1, 1997
49
lower risk in daughters of affected females is predicted, compared with daughters of affected males.
Overall, different patterns of excess maternal inheritance based on the sex of a proband's offspring would
be observed for rare X-linked traits. In contrast, for
mitochondrial mutations, excess maternal inheritance
is seen among all offspring of affected females compared with affected males. Other relative pairs also can
be used to exclude X-linked inheritance, and results
from different types of pairs should increase the power
to distinguish models.
The ability to distinguish maternal genomic imprinting from mitochondrial inheritance is more complicated than for X-linked mutations, and, in humans,
may be possible only in the simplest case of complete
penetrance and no phenocopies. As an example, assume that an imprinted nuclear mutation is inherited as
an autosomal dominant and expressed only when
transmitted through a female. Under this scenario, full
pedigree analysis of at least three generations, or use
of methods that examine relative pairs that span at
least three generations, can distinguish maternal imprinting from mitochondrial models. Thus, using
grandparent-grandchild pairs, the maternal imprinting
model predicts that the risk to the offspring of an
affected female's daughter would equal that to the
offspring of an affected male's daughter. Under mitochondrial inheritance, the risks would be 1.0 and 0.0,
respectively. Other methods using data that span only
two generations cannot be used, as the pattern of
excess maternal inheritance is the same for each
model.
So far, differentiation of models considering only
genetic or epigenetic factors have been discussed.
Other factors, such as intrauterine effects, differential
reproductive fitness, and transmission of infectious
agents may also exhibit patterns that look like nonMendelian inheritance. Thus, methods to distinguish
features of each attribute must be applied before concluding one model or another.
Fitting genetic models
Another general approach to identify a specific genetic component involved in a trait is to develop a
mathematical model of transmission, with all the complexities of the phenomena to be tested. Such work has
been done for mitochondrial and cytoplasmic inheritance in plants (e.g., see Lichter et al. (34)) and for
predominantly maternally transmitted infectious diseases (e.g., see Fine (35)). For genetic disorders in
humans, Schork and Guo (36) presented a variety of
likelihood-based models that account for the properties of mitochondrial genetics. As they comment, their
work is only a preliminary exploration of the types of
50
Sherman
possible models that could be used to identify a mitochondrial component in a complex trait. More work to
examine the power of such an approach, and the
ability to test the fit of various genetic models using a
hierarchical likelihood approach, is needed.
Another type of a model-fitting approach is that
used by Boehnke et al. (37) to explain anticipation
(observed as an earlier age-of-onset) and parent-oforigin effects seen in families with Huntington disease. This analysis was done prior to the identification of a repeat sequence mutation mechanism.
They proposed two models in which a maternal
factor acts to delay onset: a cytoplasmic model and
an autosomal or X-linked modifying gene model.
Based on the mathematical formulation of these
models, they made predictions of the age-of-onset
among different relative pairs. Subsequently, they
compared the predictions of the two models to their
empirical data on relative pairs. As both models fit
the data rather well, they concluded that more data
on specific relative pairs were needed to distinguish
their proposed models.
A similar framework has been presented by Risch
(38) using empirical risk ratio patterns among many
different relative types to obtain information about
specific models. The predictions of risk ratios were
based on the formulation of complex genetic models
involving autosomal genes. Such methods could be
extended for any of the three phenomena described
above.
SUMMARY
From this overview it can be concluded that the
understanding of the biologic properties and the development of analytic tools to identify repeat sequence
mutations, genomic imprinting effects, and mitochondrial mutations are only beginning. Development of
approaches to identify such phenomena as modifying
effects or genetic components of complex traits is a
new area of research. Not mentioned here are the ways
in which locating a gene with such properties (i.e.,
linkage analysis) would be affected if such properties
were not accounted for, or how to alter such analyses
to obtain full information. Again, this is an exciting
new area of research that will continue to motivate
epidemiologists and geneticists. Hopefully, we have
learned a lesson from the earlier conclusions of the
studies on myotonic dystrophy: keep an open mind
and never assume that the "geneticist should know
best about behavior of genes".
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