Changes in our DNA: Variant or Mutation?

Now is the time to change the language we use to describe what we find in our genomes.  For the greater duration of modern genetics, changes that could be traced back to DNA were characterized as mutations, meaning literally a change. But the word has come to connotate something deleterious, undesirable and disease-causing.  This may be simply a consequence of the historical state of technology.  Those with easily identifiable disease, some quite terrible with their onset in childhood, had recognizable syndromes known to run in families.  These were the first heritable or genetic-based diseases to be studied.  And the early discoveries indeed did find changes that were deleterious and wrought a heavy toll on their bearer and those around them.  But this new era has taught us that the vast majority of changes we now see in human DNA are  without any known impact on our health and hence likely to be harmless.

 
In the modern age of genetics where DNA sequence can be had for little effort, many variants in the genome have come to light.  The most common variant is a change in a single DNA base -- such variants are called SNP or single nucleotide polymorphisms.  Indeed, there are approximately 6,000,000 known SNPs that are relatively common  -- found at a frequency of greater than one in a hundred people --  and very likely there are 2-10 times as many found at a lower frequency.  It is absolutely true that each human genome is unique and some may argue that each genome may have a variant not seen in any other.  We can all agree there are a lot of variants and practically an infinite number of combinations of these variants assuring that we are each different from one another.

 
It is very likely that over the next twenty years scientists will not be able to associate the great majority of these variations with any role in human health.  Some will have very subtle effects on fitness but only measured over millennia. A very small percentage will have some measurable impact on our health -- these are the variations that matter to clinicians.  A greater number will have an impact on human variation we don't associate ordinarily with disease: height, muscle mass, skin color, hair, etc.  These are the variations that distinguish us from one another, often very noticeably.  But most variations will stand on the sidelines, not affecting the important functions that govern cells, tissues, and organs allowing them to function properly. 
 

There is a subset of genetic variations that can affect our biology but only under specific circumstances.  For example, many are familiar with sickle cell anemia, a disease causing a very low red blood cell blood count in patients who have inherited from each parent one copy of the sickle beta hemoglobin gene.  Carriers have one variant copy while those that have the disease carry two copies of the variant gene.  The disease afflicts primarily those who can trace their ancestry back to or live in equatorial Africa, a huge swath of land plagued with malaria.  A very sound theory has emerged from the study of those that carry one copy of the genetic variant – being a carrier of the genetic variant partially protects them from the full ravages of malaria.  This sickle cell variant would be of no value to a person living in Norway because there is no malaria in Norway.  To their physician, a carrier of this variant would not be easily recognized.  Their blood count is normal, they appear healthy.  But should they fly at very high altitude without adequate oxygen or climb to the top of a high mountain, they can develop some of the same problems with their blood as those with two variants.  In other words, it takes a very special situation – low oxygen levels –to “bring out” this trait, to reveal the underlying genetic variant.  This phenomenon is likely to be common: the impact on our biology by specific genetic variations will only be revealed under very specific circumstances.

 
While these variants may influence human biology under specific conditions, the environment is full of these circumstances.  These range from dietary variations, different exposures to chemicals, changes in temperature, or exposure to infectious disease – there are thousands of special circumstances.   All of these variations are the stuff of evolution and for some the substrate of natural selection -- if there are significant long-term changes in our environment, some of these variations may give a selective advantage to the bearer, much as sickle cell carriers have an advantage over those that have the “normal” beta hemoglobin gene. The definition of "normal" is constantly changing as our environment does.  Black skin is normal where the sun is oppressive; white is normal for colder places where the sun is less intense.  And these newer, whiter people hunted in the snow.  

 
With the drifting notion of normal, with normal having so many dimensions, it is safe to say these variations are a blessing.  These variations are the means by which we adapt, by which we survive great plagues, famines, droughts, and the wounds of wars.  Given the huge amount of diversity, at least some individuals can be assured of surviving and this gives the human race it’s most important kernel of hope, that we will survive as a species.

Let us then reserve the word mutation for those special circumstances when the change in the DNA causes a disease in a human who is eating, breathing, and otherwise functioning in standard environment.   It is worthwhile remembering that the evolution of all genomes including that of the human is without direction -- the changes in genomic DNA sequence arise primarily by neutral mechanisms such as errors in replication, recombination and drift.  Natural selection favors (or disfavors) only a tiny proportion of those changes.  Let's be thankful for our variability and not weigh it down with unnecessary judgment.