Evolutionary Neuropathology: Down Syndrome
An Analysis of the Etiological and Phenotypical Characteristics of Down Syndrome Suggests that it
May Represent an Adaptive Response to Maternal Deprivation
Medical Hypotheses, Volume 67, Issue 3, 2006, Pages 474-481
This article will suggest that the Down syndrome phenotype would have been well suited,
physiologically, for a deprived environment and that it may represent a predictive, adaptive response
to severe maternal deprivation. A trisomy of the 21st chromosome, prior to, or at conception is
responsible for Down syndrome and is known to increase in incidence with advanced maternal age.
One out of eleven mothers over the age of fifty conceives a Down syndrome baby, compared to one in
one thousand at age thirty. This article emphasizes that an older mother is more likely to die before
she is able to provide the parental investment necessary to produce an ecologically self-sufficient
offspring. Prolonged maternal investment is known to be essential for hunter-gatherers to master the
skill intensive food procurement techniques that they will need in order to become independent of their
mothers. Because Down syndrome individuals are much more likely to be born to older mothers, they
must have been routinely deprived of maternal investment in the human environment of evolutionary
adaptedness. This consistent paring of maternal deprivation to trisomy 21 conceptions, over time,
may have caused natural selection to favor genes responsible for the energy conserving traits seen in
modern day Down syndrome. These traits include muscle hypotonia, decreased cerebral metabolism,
decreased hippocampal volume, a strong propensity for obesity and growth hormone and thyroid
hormone paucity. Such a “thrifty phenotype” may have allowed Down syndrome individuals to become
independent of their mothers at a far earlier age and allowed them to forgo the skill intensive
ecological niche that non-trisomic humans are phenotypically suited for in order to take up a less
cognitively and physically rigorous one.
chromosomal nondisjunction, down’s syndrome, helping, human evolutionary reproductive ecology, life
history theory, mental retardation, trisomy
Contrary to the current view of DS as disease, I present a scenario in which DS played the role of a
protective mechanism within the ancestral human environment. To be more specific this article makes
the claim that the phenotypic expressions characteristic of DS individuals might have increased the
reproductive fitness of DS females and thereby increased the prevalence of the chromosomal
aneuploidy responsible for the DS dimorphism in the human genome.
There are other forms of non-disjunction within the animal kingdom that seem to have been made
prevalent by the forces of selection because of specific beneficial properties that they confer. The soil
nematode Caenorhabditis elegans is a species that reproduces through self-fertilizing
hermaphrodites, yet can produce functional males by means of chromosomal non-disjunction (Brenner,
1974; Hodgkin, 1987; Meyer, 2000). C. elegans is thought to have adopted the male dimorphism as a
vehicle for contingency response and increased allelic diversity. The qualities of the DS dimorphism,
as proposed here, are analogous to those of the C. elegans male in that they respond to specific
environmental contingencies utilizing non-disjunction to increase the robustness of the genepool.
Etiology of Down’s Syndrome
The clinical entity known as Down’s syndrome was recognized (Down, 1866) many years before its
etiology was determined to be related to chromosomal non-disjunction, more specifically to an extra
chromosome 21 within all cellular nuclei (Lejeune et al., 1959). Advanced maternal age remains the
most conspicuous risk factor in non-disjunction (Penrose, 1933) although several others have been
reported in the last few decades. It is important to note that the biological mechanisms that produce
non-disjunction errors in meiosis (I and II) are not well understood (Nicolaidis, 1998).
Like other forms of evolutionary medicine the propensity for DS is genetic (Antonarakis et al., 1991;
Sherman et al., 1991) with increased propensity associated with combined maternal and paternal
Prevalence of Down’s Syndrome
Down syndrome is a highly prevalent disorder that affects millions of individuals throughout the globe.
The most common identifiable cause of intellectual disability, it accounts for nearly one third of all
diagnosed cases. With an incidence of 1-2 in 1,000 births (Hook, 1981), DS, otherwise known as
trisomy 21, is the single most frequent of the autosomal trisomies in liveborns, and also the most
frequent chromosomal abnormality in children. It is clear that DS is associated with disability, but its
relative prevalence is inexplicable under current theory- unless one is to propose that DS confers a
Significant ethnic variations in the prevalence of DS might result from differences in diagnostic factors,
but more importantly it may stem from differences in population genetics (CDC, 1994; Chavez et al.,
1988; Shaw et al., 2002; Wilson et al., 1992). It is possible, and consistent with evolutionary medicinal
theory, that even slight discrepancies in the characteristics of ancestral environments may be
accountable for this uneven distribution.
The Role of Maternal Age in Down’s Syndrome
The literature provides overwhelming evidence for a relationship between maternal age and proclivity
for DS. As a mother grows older, her propensity to conceive and deliver children with DS increases
very quickly. I posit that this maternal age effect proved an apposite vehicle for the DS dimorphism
because it provides a precocial and energy efficient phenotype for children that are statistically likely to
be born to a mother that will not live to provide sufficient investment. Furthermore, women aged over
35 years are at increased risk of complications in pregnancy compared with younger women (Jolly et
al., 2000) and are more likely to die during or after childbirth (Callaghan et al, 2003).
In the vast majority of human cultures, mothers provide more direct care than do fathers (Whiting &
Edwards, 1988). In the two species most closely related to humans, chimpanzees (Pan troglodytes )
and bonobos (Pan paniscus) males typically provide little if any paternal investment, and also only
rarely affiliate with juveniles (de Waal & Lanting, 1997 ; Goodall, 1986 ; Whitten, 1987 ). Observational
studies of families in Liberia, Kenya, India, Guatemala, and Peru revealed that fathers rarely or never
engaged in parental care for their own infants (Whiting & Edwards, 1988 ). A large body of information
has led researchers to conclude that the presence of a mother, more so than a father, is instrumental in
human development and ecological viability.
Two rather large comparative studies (Antonarakis et al., 1991; Sherman et al., 1991) which analyzed
multiple DNA polymorphisms along the 21st chromosome estimated that the origin of non-disjunction
in trisomy 21 is maternal in 95% of cases and paternal in the remaining 5%. However other population
based molecular studies show that paternal errors may account for up to 9% of non-disjunction errors
(Mikkelsen et al., 1995; Yoon et al., 1996). Interestingly there has also been some evidence for a
paternal age effect (Thepot, 1996; Stene, 1981; Eichenlaub-Ritter, 1996) possibly indicating the value
of paternal investment.
The following table presents the frequencies of trisomy 21 with respect to maternal age. Please note
that the frequency of trisomy 21 increases with maternal age at a rate that is faster than the sum of all
the other chromosomal abnormalities. This relative increase is consistent with the assumption that DS
might be a preferentially selected trait.
Maternal age/ Frequency of Down’s Syndrome/ Frequency of any chromosomal abnormality:
20/ (1 / 1667)/ (1 / 526)
24/ (1 / 1250)/ (1 / 476)
30/ (1 / 952)/ (1 / 384)
35/ (1 / 385)/ (1 / 192)
40/ (1 / 106)/ (1 / 66)
45/ (1 / 30)/ (1 / 21)
48/ (1 / 14)/ (1 / 10)
49/ (1 / 11)/ (1 / 8 )
Source: Hook EB: "Rates of chromosome abnormalities at different maternal ages." Obstetrics and Gynecology
58:2882-285, 1981; and Hook EB, Cross PK Schreinemachers DM: "Chromosomal abnormality rates at
amniocentesis and in live-born infants." Journal of the American Medical Association 249:2034-2038, 1983.
The following table presents the frequency of trisomies for each chromosome and the number among
both spontaneous abortions and live births. This table shows that Down syndrome is by far the most
frequent form of trisomy. It is also interesting to note that both trisomy 13 and trisomy 18 are also
associated with severe mental retardation.
Chromosomal Trisomy/ Number of Spontaneous Abortions/ Number Among Live Births
1 0 0
2 159 0
3 53 0
4 95 0
5 0 0
6-12 561 0
13 128 17
14 275 0
15 318 0
16 1299 0
17 10 0
18 233 13
19-20 52 0
21 350 113
22 424 0
It is also interesting to note that the maternal age effect does not increase after age 49 (Hook, 1981).
This suggests a reproductive strategy for the following reason: The abatement in the maternal age
effect is relatively consistent with both the average age of menopause, 50 to 52 years (Mackay et al.,
1983) and the average life expectancy for modern hunter-gatherer groups as seen in the following
Life History Parameters for Hunter-Gatherers
Group Terminal Age
Hadza Female 54.7
Hadza Male 52.4
Hiwi Female 51.3
Hiwi Male 51.3
!Kung Female 56.5
!Kung Male 56.5
Sources: Blurton Jones N, Smith L, O’Connell J, Hawkes K, Samuzora CL. 1992. Demography of the Hadza, an
increasing and high density population of savanna foragers. Am J Phys Anthropol 89:159-181. and Hill K,
Hurtado AM. 1996. Ache life history: the ecology and demography of a foraging people. Hawthorne, NY: Aldine
de Gruyter. and Howell N. 1979. Demography of the Dobe !Kung. New York: Academic Press.
It is also important to note that it has been shown that the trisomies associated with maternal age may
not be due to increased rate of nondisjunctions during conception. A review of studies on the effects
of maternal age on trisomy 21 conceptions written by Raymond Kloss and Randolph Ness suggests
that the origin of the trisomies lies not with an increase in nondisjuctions, but a from a decrease in
rejection of trisomy zygotes (1992). This finding suggests that the pronounced association between
trisomy 21 and maternal age is more deliberate, and is indicative of a reproductive strategy (1992),
because it is not simply due to germ cell mutations
Other Risk Factors that May be Environmental Cues in the Fetal Programming of DS
Other risk factors associated with DS provide corroboration. A cluster investigation reported that short
pregnancy interval is implicated as a risk factor for DS (Brender, 1986). It seems logical that mothers
who have more than one baby in a short time interval would be statistically less likely to provide
sufficient maternal care because their time and resources will be divided. Furthermore, one would
expect that a mother would continue to provide sufficient care to the baby that she has already invested
in previously, and possibly insufficient care to subsequent offspring. Other reports have strongly
associated anovulatory activity followed by conception with increased occurrence of DS (Jongbloet et
al., 1982; 1985). These findings can be interpreted in a similar way. Anovulatory activity, or
amenorrhea, is usually caused by either pregnancy or lactation, and it is conceivable that this effect
may have been selected for because of the difficulty associated with allocating maternal investment to
two closely spaced infants. Many studies have found that sudden infant death is similarly positively
correlated with short pregnancy interval; this may be an analogous corollary of diminished maternal
investment. Another study reported that firstborn individuals experience a lower risk of DS (Stoll et al.,
1990). If this difference is significant it would be consistent with the assumption that the frequency of
DS is related to maternal investment, because it is a common observation that firstborns receive high
amounts of investment relative to subsequent children. This epidemiological data frames the DS
dimorphism as part of a quantitative reproductive strategy.
Another interesting pattern is derived from reports that have found an association between risk of DS
and advanced age of the maternal grandmother at the mother’s birth (Mikkelsen, 1995; Aagesen et al.,
1984)- after correction for maternal age. There is growing consensus in the anthropological literature
that the presence of a grandmother, especially a maternal grandmother (Sear et al., 2000; Voland et
al., 2002) has a variety of positive effects on a growing child’s rate of productivity and life expectancy
(Hawkes et al., 1989; 1997). If the grandmother was very old at her daughter’s conception then it
follows logically that she is likely to be quite old at the time of her grandchild’s conception. It would also
follow logically that an older grandmother would be less likely to provide grandparental investment
before she dies.
The Protective Functions of Down’s Syndrome
DS babies have a very low metabolism and this might have enabled them an atavistic ability to
conserve calories and thus avoid starvation.
It is well established that the brain and nervous tissue in general is metabolically expensive (Aiello, L.
C. 1995; 199-221). In fact the mass specific metabolic rate of brain tissue is over 22 times the mass
specific metabolic rate of skeletal muscle (Aschoff et al., 1971). The microencephaly, or small brain
size seen in DS individuals may in fact be an advantageous decrease in this metabolically expensive
Brain volume and weight are well documented to be diminutive throughout the maturational timeline in
DS individuals (Crome, 1972; Sylvester, 1983). A study limited to adults determined that the average
brain weight in DS adults is 76% of normal, with an average brainstem and cerebellar weight 66% of
normal (Crome et al., 1966).
The volume of the hippocampus is significantly smaller in DS subjects than in normal comparison
subjects even when total brain volume is controlled for (Jernigan et al., 1993; Kesslak et al., 1994;
Aylward et al., 1999). Accelerated volume reduction in the hippocampus and amygdala are also
hallmarks of aging in Down’s syndrome (Wisniewski et al., 1985; Raz et al., 1995; Prasher et al.,
1996). All individuals with DS over the age of 40 exhibit the neuropathological characteristics of AD
(Wisniewski et al., 1985).
Reports have indicated that the resting metabolic rate of both children and adults with Down syndrome
is significantly lower than those of normal individuals (Luke, 1994; Allison, 1995). This is thought to
partially explain the high proclivity for obesity in DS groups as observed in modern times (Cronk,
A hominid, or early human, that was mentally retarded and had a vastly lower metabolism would
probably not be well adapted to the rigorous environmental niche of its peers. It would probably not
have been able to catch large or small game, and would have had trouble extracting roots, tubers and
other difficult to obtain, high calorie foodstuffs. The ancestral DS diet would have likely consisted of
leaves, dried fruit, insects and other easy to extract foods. It is conceivable that the DS diet would
have been likely supplemented by the efforts of close kin and community members, however, it is likely
that the DS diet more closely resembled the diets of our primate ancestors. DS individuals resemble
our earlier ancestors in terms of brain size, body size and metabolism so it seems natural that they
would have filled a similar ecological niche.
DS (Devlin et al. 2004) and other heritable forms of MR are associated with hypertelorism. It makes
sense that an MR individual would be less susceptible to ambush if they had wider peripheral vision.
Wider set eyes should prove valuable for a scenario vigilance strategist and it is clear that many
vigilance strategists like mammalian herbivores, reptiles, amphibians and fish also exhibit
hypertelorism- their eyes are on the sides of their heads. We know that MR humans have working
memory and attention deficits and so it makes sense that they might forgo the benefits of
hypotelorism- they would be less likely to benefit from tool making or close perceptual work.
It is also interesting to note that Down Syndrome individuals have a few strange phenotypic traits that
some might see analogues of in chimpanzee morphology. DS individuals are much more likely to
have small noses, flat faces, and a larger space between big and smaller toes (the sandal gap).
Perhaps even more intriguing, DS individuals are much more likely to have a simian crease in their
hand (Devlin et al. 2004)- which all monkeys and apes but very few humans have. Analysis of the
genes for such morphological traits may help researchers estimate when the DS dimorphism arose
during the time that humans diverged from the common ancestor that they share with apes.
The Chinese Human Genome Center has spent much time studying the genomic divergence between
humans and primates primarily because, as they assert, it “may provide insight into the origins of
human beings and the genetic basis of human traits and diseases.” They chose to compare the genes
located on the 21st chromosome in humans to the corresponding genes of chimpanzees, orangutans,
gorillas and macaques. The findings of one study (Jinxiu et al., 2003) identified the number of
nucleotide differences, and the differences in coding promoter, and exon-intron junction regions
between humans and the aforementioned apes. Using a bioinformatics based approach they
concluded that the discrepancies between the genes found on human chromosome 21 and the genes
found on the homologous regions in chimpanzees suggest that chromosome 21 arose due to the
presence of “purifying selection.” Importantly, the genes related to both DS and Alzheimer’s disease
are both located on the 21st chromosome, a very small chromosome that seems to contain a relatively
small number of genes. This knowledge makes one wonder if the 21st chromosome in humans
evolved to house genes that could counteract a fundamental reliance on intelligence.
Reproduction in Downs Syndrome Individuals
It is very difficult to find precise information about DS reproductive sterility and fertility yet it is well
known that the majority of DS females are fertile and the majority of DS males are sterile. According
to national statistics 85% of females with DS are able to procreate and yet less than 5% of males are
able to procreate. These findings make sense in terms of evolutionary and sociobiological theory.
Remember, a DS baby fertilized by a DS father would decrease the reproductive fitness of the normal
mother (because she is forced to carry an invalid to term despite the fact that there are no biological
limitations on the investment that she can provide), so it makes sense that the majority of DS males
are sterile (because they would be rejected by females- female choice and sexual selection).
However, a DS mother would be able to increase her reproductive fitness and the reproductive fitness
of a normal male if she carried his baby to term. Furthermore, half of her babies would be normal-
without trisomy 21. For these reasons it is reasonable to assume that DS males would encounter
difficulty finding receptive females whereas DS females probably would not encounter difficulty in
finding receptive males. This is evidenced by the fact that DS females in modern times have notorious
difficulty related to sexual advances from normal males. One study reports that 72% of sexual abuse
victims that are mentally retarded are women, and that the majority, 88%, of perpetrators are men
This implies that DS females would have been the driving force behind the selection for trisomy 21,
and that their progeny would carry genes for increased proclivity. The sterile males may though may
still have been able to increase their reproductive fitness, and thus the human proclivity for DS, by
aiding their kin and increasing their inclusive fitness.
The concept of Darwinian Medicine has become an increasingly emergent theme in medical science
and it has deeply impacted the viewpoints assumed by immunologists and pathologists. It has
become well accepted that certain diseases can be precipitated by specific physiological or
immunological adaptations which arise to combat more pernicious diseases. For example sickle cell
anemia is an unfortunate complication of an evolutionary response to malaria just as cystic fibrosis is a
similar response to cholera. Individuals that have a moderate genetic propensity for such adaptive
responses are able to successfully combat the specific disease. However, those that have a strong
genetic propensity (often characterized by homozygosity) for such a response can experience
unfortunate, debilitating complications. It is interesting to note that the propensities for Down
Syndrome are genetic, with severe complications associated with combined maternal and paternal
Taking a Darwinian viewpoint one might decide that if these disorders conferred no benefit then those
that exhibited a high proclivity for them would be more likely to die. If these disorders were only
disadvantageous, wouldn’t evolution have selected those humans with more cognitively robust
Considerations Related to Future Research
The hypothesis promulgated by this article cannot be adequately substantiated because of the dearth
of related research. As such, like most discussions related to macroevolution, this article has resorted
to inferring process from pattern. It is evident that much more work is needed to define the parameters
of the relationship between DS and human reproductive strategy.
To continue to section III please click here.
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