Ross Finesmith M.D.
Genetic mutations are the structural force in the propagation of all species. A spontaneous mutation allows a
species to more successfully compete and survive in their environment. A classic example is the mammalian
ancestors of the current day whale species. As the earth warmed and survival depended on adjusting to the
seas, predecessors of today’s whales gradually demonstrated improved hunting and mobility capabilities in
the ocean as a result of genetic mutations in their limbs, that allowed them to be more adaptive in water and
thereby more likely to survive and thrive. The same can be described in the evolution of some disease
A protective mutation can be described as a spontaneous genetic variation that has proven to be protective
with regard to specific diseases. Occasionally a protective mutation results in a genetic disorder. One of the
first discoveries of this phenomenon was in the protective effect of Sickle Cell disease against the infectious
effects of malaria. In this case, the genetic mutation causing Sickle Cell disease protected the afflicted
individual from the effects of malaria.
Sickle cell (SC) anemia gene is prevalent despite the high mortality rate. Malaria is one of the most
prevalent parasitic infections in the world. SC anemia results from the homozygous pattern (HbAS) and is
fatal in children if not treated.
The heterozygous gene pattern (HbAS) is referred to as the sickle cell trait.
Approximately 225 million cases are recorded each year and approximately 1 million die each year.
persistent survival of the SC gene is, in part, due to its protective factor against the effects of malaria.
HbAS is prevalent in malaria endemic regions such as western Africa.
Well before the relationship between
SC and malaria was discovered, Haldane postulated that the Darwinian theory predicts, “that even if a gene
offering protection against (a) parasite were otherwiseharmful, its frequency would increase when
apopulation was exposed to the parasite.”
This has been confirmed in several reports.
Population based and epidemiological studies that have confirmed that HbAS is protective against morbidly
and mortality associated with malaria. HbAS heterozygotes do contract malaria, but are found to have lower
counts of the parasite infected red blood cells (RBC’s) and have been found to infrequently have severe
malaria. These forms are cerebral malaria and severe anemia associated with the malaria infection.
Current evidence suggests that the protective effective of the gene pattern HbAS against malaria is based on
two mechanisms. The growth rate of the malaria parasite has been shown to be greatly reduced in HbAS
RBC’s compared to normal cells.
The polymerization of the HbAS hemoglobin structure inhibits replication
of the parasite. In addition, there is increased phagocytosis of parasite infected RBC’s in those with the
sickle cell trait by the infected persons immune cells.
Specifically, there is an enhanced immunoglobulin G
(IgG) response to the surface antigens on the RBC’s of the malaria-infected cells in persons with the HbAS
Alzheimer's Disease (AD) is the most common type of dementia. There was an estimated 4.7 million individuals aged
65 years or older with AD dementia in 2010.
As deaths due to heart disease, cancer and stroke have decreased in
the past decades, deaths directly attributed to AD have raisin by 46%.
AD has become the fifth leading cause of
death in Americans aged 65 and older. As medical advancements prolong our lives and the progression of the “baby
boom” generation, the projected prevalence of AD in the United States by 2050 is 13 million.
Alzheimer’s disease is a multi-faceted condition and the etiopathology is not completely understood at this time. The
clinical course of AD is also complicated by the co-morbid presence of other neurological condition in most
patients.This is supported by the fact that over 50% of neuropathological findings at autopsy in individuals established
to have had meet clinical criteria for AD, showed neuropathological evidence of additional neurological conditions.
These co-morbid neurological findings were consistent with Parkinson’s disease, stroke and Lewy Body disease.
AD research has focused on β-amyloid accumulation and plaque formation. A small percentage of AD patients are
found to have a known associated genetic mutation. Our current understanding that the mutations causing AD are
genes responsible for the amyloid precursor protein (APP), presenilin 1 and presenilin 2.
These genes are occurred is
what is referred to as autosomal dominant (ADAD). The clinical progression in these genetically understood individuals’
progress in the same course in those in the majority of AD patients without these mutations. Therefore, the production
in these mutated genes should provide critical information in unraveling the pathologicalprocess and future effective
therapeutic interventions for all patients with the clinical manifestations of AD.
The primary neuropathological feature in the brains of AD is the β-amyloid plaques.
Excessive β-amyloid is formed
when mutations occur in the enzymes that cleave APP.
Several mutations have been found to form more toxic form
of β-amyloid or increase the propensity to aggregate in plaque form in the brain.
In a recent study of genome
sequence data from 1,795 individuals from Iceland, the coding mutation was found that protects against the
development of AD. A67ST is a mutation found near the gene for theaspartyl protease β-site APP cleaving enzyme 1
(BACE1), which is involved in the sequential cleaving of APP. The A67ST associated mutation results in a 40%
reduction of amyloid peptides that are responsible for forming plaques in AD.
Icelanders with this mutation were five
times more like to reach the 85 with meeting the criteria for AD. The A67ST associated mutation results in a single
amino acid substitution in APP and appears to prevent the activity of BACE that usually enzymatically cleaves APP in
smaller β-amyloid components. This findings support the pursuit of discovering strategies to reduce β-cleavage to
prevent the progression of AD. This same mutation was found to protect against cognitive declinein neurologically
normal individuals over the age of 85 without the signs of clinical AD.
The specific genes responsible for the variants of apolipoprotein E (APOE) have also been found to contribute to an
individual’s risk of developing AD.
Each parent contributes and APOE gene, ε2,ε3or ε4. Although ε4 is associated
with an increased risk for developing AD, several studies have reported a protective or a reduction of AD risk
associated ε2. APOE genes code for the proteins that carry cholesterol in the blood and the mechanism of action of the
this proteins role in AD is not completely understood at this time.
Osteoporosisis the most common pathological bone condition in the United States and the world.
Osteoporosis is characterized by decreased bone density, withdeterioration of bone architectural, resulting in a
propensity for fractures.
Osteoporotic fractures occur in 2 million Americans each year and an estimated 9
The incidence is increasing, since populations are living longer. The risk of developing
osteoporosis increases with age and is significantly more common in women.
Genetic and environmental factors both contribute to the development of this condition.
density has been shown to have significant heritability and is a major predictor of developing osteoporosis
and experiencing osteoporotic fractures.
Maintaining bone function requires constant remodeling that involves continuous destruction and resorption by
bone osteoclasts. Adult bone mass is determined by maintain a homeostatic balance between osteoclastic
bone resorption and osteoblastic bone construction. The osteoclast rebuilds an elaborate matrix that
subsequently is mineralized. The bone-remodeling activity and the number of osteoclasts, in a given individual,
is determined by cell lineage allocation, proliferation of osteoclast precursors and the efficacy of mature
A recent discovery in bone formation signaling revealed that the low-density lipoprotein receptor related protein
5 (LRP5) plays a novel role in bone formation. Mutation in the LPR5 gene was first found when a family
kindred with a hereditary skeletal disorder of high bone mass (HBM) without any other physical
The HBM trait was mapped a single mutation marked G17V, for LRP5, in chromosome
This mutation was confirmed in a second family with a HBM skeletal condition. A LRP5 gene mutation
causing a reduction in bone formation activity was found as a locus for osteoporosispseudoglioma syndrome
Currently, there is no dataregarding the frequency of LPR5 mutations since the understanding of its role in
bone formation is relatively recent. LRP5 is expressed in most tissues at a low level and until now, LRP5 was
not known to influence bone formation. LPR5 activity was initially discovered as a function of apolipoprotein E
affinity as were other LDL-receptors subtypes.
However, additional studies found the LRP5 activated the
Wingless/Wnt signaling system in bone.
The activation of the Wnt canonical pathway in bone cortex
stimulates internal bone formation.
Wnt signaling activation in osteoblast precursor cells results in promoting
osteoblastic cell differentiation and increases the number of cells in bone. Therefore, mutations in LPR5 can
lead to a reduction of activity or an over-activation of the WnT signaling system and corresponding bone
The LRP5 gene has been shown to be involved in both osteoporosis syndromes and the HBM phenotypesand
is an important regulator of peak bone mass in vertebrates. Increase in LPR5 function leads to greater bone
formation, and reduced function results in osteoporosis. At risk persons for osteoporosis that may have low
calcium intact, a centenary lifestyle, or medical condition that reduces bone mass, can be protected with a
LPR5 mutation causing increased bone formation.
In the 2013 Executive Summary, the American Heart Association
estimated that 15.4 million (6.4% of the
U.S. population) had coronary heart disease (CHD) in 2010 and 7.6 million (2.9%) suffered a myocardial
Multiple epidemiological studies have established hyperlipidemia, smoking, diabetes and
hypertension as the most significant risk factors for developing CHD.
It is estimated that over 98 million
Americans have a total cholesterol level greater than 200 and almost 32 million levels are greater than 240.
The types of lipoproteins are very low-density lipoprotein (VLDL), low-density lipoprotein (LDL) and high-
density lipoprotein (HDL). Each has a distinct content of apolipoprotein, metabolic and functional properties.
LDL has long been linked to the formation of atherosclerosis and CAD. The pathogenic factors are its readily
endothelial permeability, proteoglycan binding and high degree of oxidizbility.
Several subtypes of LDL
have reduced liver clearance from the blood stream and circulate in the vascular system for longer periods
than other lipoprotein classes. The proteoglycan molecules in the endothelium bind to LDL and facilitate
uptake into the intima of the vessel contributing to the atherosclerotic plague formation.
properties of LDL also include by the oxidized form of LDL, which stimulates foam cell formation and
inflammation of the arterial wall intima.
This phenomenon has been shown to clinically correlate to the
severity of CAD in patients.
The clinical benefits of reducing serum LDL by diet and pharmalogical intervention have been proven in
multiple studies. In a meta-analysis study of 58 randomized trials evaluating the effects of satins on LDL and
CAD revealed that statin use resulted inan average LDL reduction of 1.8 mmol/l, a 60% risk reduction of
suffering an ischemic cardiac event and a 17% risk reduction of stroke.
Diets in high fiber, fruits and
vegetables with lower amounts of saturated fats result in a reduction in serum LDL levels and risk for heart
It has been estimated that a 6% reduction in total cholesterol level by dietary modifications would
result in a 24% reduction in coronary deaths in the U.S.
The LDL receptor plays a central role in removing cholesterol from the circulation. The common-type LDL
receptor binds with circulating LDL and internalizes the molecule into the cell.
Inside the cell the LDL releases
the cholesterol into the cytoplasm. The raise in intracellular cholesterol level provides a negative feedback
mechanism that results in inhibition of cellular release of cholesterol into the blood stream. In the 1970’s a
cohort with familial hypercholesterolemia (FH) was found to have LDL receptors that did not bind to circulating
LDL and thereby having no negative feedback influence on cholesterol release.
These patients were had total
cholesterol levels between 300–1500 mg/dL. Overall, a reduction in LDL receptor function clearly results in
hypercholesterolemia and contributes to CAD.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is produced by liver cells and plays an important role in
regulating LDL cholesterol levels.
In the common form, PCSK9 binds to the LDL receptor resulting in the
destruction of the receptor and therefore a reduction in LDL serum clearance.
A mutation that results in
overproduction ofPCSK9 has been found to dramatically increase LDL-cholesterol serum levels in patients with
autosomal dominant hypercholesterolemia.
Conversely, a protective mutation that produces lower amounts
of PCSK9 results in preservation of LDL receptors and leaves receptors available to bind and clear LDL
molecules from the blood stream. This protective mutation,that results in lower blood concentrations of PCSK9
and LDL cholesterol, has beenidentified in humans.
In a large study in Copenhagen, 2.8% carried a
PCSK9 mutation that resulted in a reduction in LDL cholesterol levels and a significant reduction in risk for
subsequent ischemic heart disease.
Human Immunodeficiency Virus (HIV), and its sequela Acquired Immunodeficiency Syndrome (AIDS), was
initially reported in the 1980’s and continues to be the world’s most serious infectious disease. There are
approximately 34 million people that are HIV positive almost 30 million have died from AIDs. Since 2001 there
has been a 50% decline in new cases, however this still represents 2.5 million new infections recorded in 2011
HIV/AIDS infection and disease progression are influenced by multiple factors. The role of the CD-4
chemokine receptors plays a critical role in influencing HIV transmission and multiplication in the body.
Chemokine receptors on the surface of white blood cells and are involved in binding to specific cells in the
body. C-C chemokine receptor type 5 (CCR5) is common receptor subtype and normally is involved in
stimulating an inflammatory response to infection. CCR5 was discovered to play a fundamental role in entry of
the HIV into T-cell. Once the HIV enters the blood stream it readily binds to CCR5 receptors and enters with T-
CCR5-D32 is a mutation of the CCR5 gene, which produces a protein receptor that does not bind the HIV. It is
estimated that between 5-14% of individuals of Northern European descent carrier one or both alleles’ of the
protective mutation. The two copies (homozygote) for the CCR5-D32 mutation has been shown to
dramatically protect against HIV infection. Individuals homozygous for this allele can be exposed HIV and not
contract the infection or develop AIDS.
One copy of the CCR5-D32 allele is not protective against
transmission of the disease but delays the progression rate by up to 2 years.
An genetic analysis of 4,166 individuals revealed a cline of CCR5-Δ32 allele frequencies of 0%–14% across
Eurasia, however the variant allele was absent in native African, American Indian, and East Asian ethnic
Additional studies have shown the protective CCR5-D32 mutations is most common in Caucasians
and essentially absent in those of Western and Central African descent as well as those in the Japanese
Our current understanding is that this protective mutation may have been present for several
hundred years and continues to increase in frequency, as HIV is a strong selective process.78
Infectious diseases have plagues the world for thousands of years and killed millions. The agents change
and are genetically modified over time to increase there chance of survival. Norovirus (NoV) has become a
major cause of gastroenteritis over the recent decades. In a prospective study of adults with acute
gastroenteritis (AGE) requiring emergency department (ED) visit, 389 subjects were entered into the diagnostic
study. Stool samples and serum samples were collected in in the ED and 3 weeks later. NoV was the most
commonly detected pathogen and isolated in 26% of specimens that a pathogen was detected.
In a 2010
England study of the community incidence of NoV was estimated that there are 2 million episodes of NoV-
associated episodes of AGE per year in that country.
The virus transmits and progresses especially rapidly in
areas where people are in close proximities such as schools, military barracks, college dormitories, hospitals
and nursing homes. Transmission occurs primarily person-to-person contact but also via food, water and
fomite contamination. There were several factors that support the concept of a protective genetic component
that prevents infection in some. This includes an attack rate or rarely above 70%,
small inoculation of NoV is
required for infectious transmission and the same individuals may not become infected despite many-repeated
In is the current understanding that defense against NoV is enhanced those that do not secrete (non-secretors)
histo-blood group antigen and are less likely to become symptomatically infected by NoV.
several studies have shown secretor positive patients are more susceptible to NoV infection.
mutation that is associated with the non-secretor status is the FUT2 gene.
FUT2 gene been identified in
several studies to be highly protective against NoV infection.
Multiple sclerosis (MS) is a chronic autoimmune neurological disorder that is characterized by intermittent,
isolated and localized episodes cerebral white matter demyelination. Autoantibodies target the epitope on the
surface of oligodendrocytes that produce the insulating myelin for neurons in the brain.
A cytotoxic sequence
follows that results in oligodendrocyte cell death, demyelinated neurons neurological dysfunction.
clinic in has recorded the incidence of MS in the Olmsted County Minnesota for almost 100 years. The
published rate was 7.5 per 100,000 person-years with little change in the past 20 years.
A recent 10-year
surveillance study of personnel in the U.S. Armed Forces revealed a rate of 12.9 per 100,000 person-years.
There are multiple theories of the risk factors, but limited information on possible genetic factors. Prevalence
rates vary throughout the world. Relatives of patients with MS have been shown to be at increased risk of
developing the condition
. ApoE has been extensively studied in lipid disorders, CAD and ASD. The
inflammatory cerebral processes of AD have similarities to those found in MS. Initiallythe data from studies
was conflictingregarding the role ApoE may play in the risk of developing MS. In a recent meta-analysis of 20
qualified studies, involving 4,080 MS cases and 2,897 controls,evaluated the association of ApoE gene
polymorphism and MS. The ApoE ε2 mutation was associated with an increase risk of MS, but ApoE ε3/ ε4
was found to have protective effects against developing MS.
Although the role of ApoE is well understood in
lipid and cholesterol transport, the role in MS is not currently understood. There is a described role of ApoE in
the development of the brain and its repair following injury and may be discovered to be related to
immunogenic lipid targets on the lipid dependent oligodendrocytes.
The Future of More Protective Mutations
There are several protective, or enhancing, genes that have been discovered in animal models are likely
similar to genes humans possess. These discoveries may provide a pathway to understanding human
mechanisms in handicapping and disease states.
Short- and long term memory have purposes as well as different physiological mechanisms. The more
permanent long-term memory requires adaptive physical neuronal changes that “encode” the new experience
or learned behavior. This, in part, depends on an individual’s neuronal plasticity that allows for more efficient
from gene expression and specific protein modifications associated with the new memory
The most common protein modification in learning is phosphorylation. Long-term potentiation
(LTP) and long-term depression (LTD) are cellular models used to study long-term memory at the neuronal
Activity, or agents, that inhibit mRNA and protein synthesis have been shown to suppress LTP in in-
and memory in animal models.
It is currently understood that elF (a translational initiation factor) phosphorylation suppresses cellular mRNA
and inhibits LTP, and theoretically learning.
A process that enhances elF complex
transcriptional activity, or limits the phosphorylation of elF units, improves and sustains LTP.
This model has
been established in animal memory studies of “knock-out” mice.
Additional protective mutations discovered in animal models include retinitis pigmentsa,
induced hearing loss
, chemotherapy cellular protection,
and Parkinson’s disease.
Gene mutations that improve the fitness of a species are likely to increase in frequency as an organism
survives, thrives and produces offspring. Mutations in disease states also occur randomly and the new
mutation make counteract or mute the dysfunctional activity of the genetic disorder. This may be the case with
Alzheimer’s Disease where our current understanding is that genes on chromosome 21 contribute to the
pathological production of APP and subsequent excessive β-amyloid deposition in the brain. Individuals that
inherit, or spontaneously generate, the A67ST mutation will have less β-amyloid production despite the genetic
production of APP.
In addition, survival of a species is enhanced if a genetic mutation protects against environment conditions or
behaviors that raise the risk of a disease onset. This is seen in some types of CAD and osteoporosis. High fat
disease and sedentary lifestyle greatly increase morbidity and mortality due to atherosclerosis and CAD. High
serum cholesterol levels have less health risks n persons with the PCSK9 mutation that produces less of this
protein. A similar case is made for osteoporosis where poor calcium intake and a sedentary lifestyle increase
the risk of the disease. The LPR5 stimulates the Wnd system, which increases osteoblastic activity and
increases bone production.
In this paper we describe the protective effects of the FUT2 mutation against NoV infection. This raises the
question as to whether this phenomenonoccurs more frequently that established as it is noticed
regionalinfections “die-out” or run their course over time. Genetic mutations or protein modification may
possibly paly a role in these phenomenon. In addition, it is not uncommon to know someone who rarely
contracts a cold or the prevalent strain of influenza. Is it possible these individuals have a protective mutation
that provides the “non-secretor” protection against other viruses?
Just as Darwin’s theory provides a framework for genetic survival, protective mechanisms can play a vital role
in the survival of species against fatal disease states. Continued efforts in the genetic sciences will clearly
provide more gene mutations that some cohort harbor that protect them from disease other disease states.
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