Let's see...I started thinking about hair color when I last saw Aunt Molly. She has brown hair. She married Uncle Sven, who's blonde, and all five of their kids have brown hair like Aunt Molly. But her sister, Aunt Jess, also has brown hair, and Uncle Tage has blonde hair, but their son is blonde! I wondered why Aunt Jess's son has blonde hair, instead of brown like Aunt Molly's children do.
I drew a little diagram of the two families, like this:
After looking into the inheritance of blonde hair and brown hair in Labrador Retrievers, I thought it might make sense to think of each of us (including the Labrador Retrievers) inheriting genetic factors from our parents, one from Mom and one from Dad. I looked into inheritance of color patterns in sheep, which seems to confirm this idea. From the brown and blonde dogs, it looked like the best way to explain the observations was this way:
- inheritable factors--genes--are information for enzymes
- the gene responsible for brown hair color probably produces an enzyme that makes the brown pigment
- there are different "versions" of this gene--which geneticists call alleles, rather than "versions"--that produce enzymes with more activity or less activity; those with more activity make more of the brown pigment
- therefore, dark hair is "dominant" to light hair, but brown-haired individuals may carry the "blonde version" of the hair color gene; it's just "masked" by the more-active version of the gene that they inherited from the other parent
Does this model help me understand my family? Let's work through the drawings I made before, but this time add a drawing to indicate the versions of the genes (i.e. alleles) that each person carries.
Uncle Sven and Uncle Tage are both blonde. They must each have two copies of a blonde version of the hair color gene. I can't quite tell about Molly and Jess; they both have brown hair, and could have a blonde version of the gene plus a brown version of the gene, or they could have two copies of the brown version.
But Jess has a blonde-haired son! She must have a copy of the blonde allele.
We still can't tell about Molly, though. She could have both blonde and brown alleles, but all of her children happen to have inherited her brown one. Or, she could have two copies of the brown allele. With so few children, that seems like it could be possible (now, if she'd had a thousand children, we'd be better able to make an argument based on the numbers, but 5 just isn't enough).
Let's see if we can re-draw these diagrams so that they can show the alleles the people have, and not just their overall hair color (i.e., to show their genotype, rather than phenotype). Perhaps, as a simple way to represent each allele, we can just divide the male and female symbols in half, and fill each half in with a color that represents the allele. If we can't determine which version of the gene to indicate in the drawing, let's just use a question mark -- like this:
Using these symbols, our diagrams would look like this:
Tage and Jess
The Drawing Based on Hair Color
Molly and Sven
The Drawing Based on Hair Color
A Drawing That Reflects the Alleles They Carry
A Drawing That Reflects the Alleles They Carry
This looks like a method we can use here...Tage is blonde, and must have received a blonde allele of the haircolor gene from each parent, if this allele is recessive to brown. (The blonde allele was recessive to brown in our study of Labrador Retrievers. We hypothesized that this resulted from the brown enzyme producing more brown hair pigment than the blonde enzyme. We also hypothesized that the black allele produces an enzyme with even more activity, and produces even more pigment--so black was dominant to brown. These genetic relationships make sense for these hair colors, so we'll use the same logic here.)
Jess has brown hair, but her sone has blonde hair, so she must have one brown allele and one blonde allele. We can represent this easily in our diagram.
For Aunt Molly's family, it's not so clear. All of her children must have inherited a blonde allele from Uncle Sven. For her children to have brown hair, they must also have inherited a brown allele from Molly. But, we can't tell whether Molly has two brown alleles, or whether, like Jess, she has one brown and one blonde. She may have a blonde allele, but her children just happen to have inherited the brown allele.
(With only 5 children, we just can't tell...but if she had a thousand children, it would be more likely that at least one of them would have inherited the blonde allele, if she has it. I guess humans just don't have enough offspring to make studies of inheritance very easy. It's a good thing we used Labrador Retrievers to start our study of hair color, so we could examine larger numbers of individuals.
Hmmm...I wonder if there might be other species of plants or animals that might have thousands of offspring, so we could really get a handle on this. Perhaps, after re-examining my family, it would be good to think about some kind of "model system" where we can really study inheritance easily.)
Looking at Aunt Jess's family, we've figured out something we didn't realize when we first thought about this. Aunt Jess must have a blonde allele, even though she has brown hair. That's the only way, it seems, that she could have a blonde son. When we thought about this before, we had to work back several generations to discover an ancestor who had blonde hair. With the knowledge of genes that we gained from our studies, we can now tell right away that Jess must have the blonde allele. Let's redraw a more extensive diagram of the family tree, using this new method of illustrating the alleles that each person carries:
With this diagram, we can see that my great grandmother was blonde, and that Jess must have inherited her blonde allele from her, through her father. But it's still fairly difficult to determine who, in this family, is homozygous for the brown allele (i.e. has two copies of that allele) and who is heterozygous (i.e. who has one brown allele and one blonde allele). We've had to leave many question marks in the family tree.
What if we carry this study on for one more generation? Are any of my children blonde? Here's the family tree, extended another generation:
My daughter has blonde hair, and mus therefore have two blonde alleles. That means that I must have inherited my great-grandmother's blonde allele from my dad. It also tells us that my husband must also have a blonde allele.
This is interesting. It looks like we can follow the inheritance of a recessive allele if there are a fairly large number of people who carry it. As with myself, my husband, my dad, and Aunt Jess, we can make a good case for each of us carrying a blonde allele. We can infer this because one or more of our offspring or later descendents shows the recessive phenotype (i.e. has blonde hair). But if we know only that someone shows the dominant phenotype, and we don't have "extra clues" from looking at their offspring, all we can conclude with confidence is that they have at least one dominant allele (in this case, the brown allele).
There is a great deal of genetic diversity among humans; we all look different from one another. This must reflect the fact that genes are the chemical compound, DNA--and are therefore subject to chemical damage, which can cause changes in the DNA sequence. Each of us carries a number of DNA sequence changes relative to our parents, in addition to the reshuffling of alleles that occurs during meiosis. These DNA sequence changes are mutations; most have little effect, but some create new alleles that are recessive to the more-common alleles in the population. Some of these recessive alleles interfere with physiology, cellular biochemistry, or other important functions--but only affect those functions in individuals who inherit the recessive allele from both parents.
In isolated, small communities, there is a reasonable chance that two people who marry may have a common ancestor; perhaps this ancestor was their great-great grandparent, or great-great-great-great grandparent. In such an instance, it is possible that both husband and wife may carry one of these recessive alleles; their children may receive this allele from both parents. It is from this kind of common ancestry that unusual traits sometimes appear in small, isolated communities. One of the more famous is blue skin. Unfortunately, many such recessive mutations interfere with embryonic development or neuronal function, causing problems in growth and learning.
We refer to this as inbreeding--breeding among individuals who are more or less closely related. There are strong, instinctive taboos (in many species, not just in humans) against close inbreeding (sibling matings, for example). But in a small, isolated community it takes relatively few generations before most people share distant ancestors with someone else in the community. Unusual recessive traits are more likely to arise in such communities.
In large communities, and especially in cities with international populations, outbreeding, or out-crossing, is far more likely. There are simply more people to choose from in marriage, and they are from widely differing backgrounds. Let's consider the last of the family tree diagrams from the initial investigation of hair color in my family, but redrawn to indicate the haircolor alleles that we can indentify. As before, we'll indicate "newcomers" to the family with arrows. We'll color the arrows blue for individuals whose haircolor genotype we cannot fully determine, and red for those whom we can figure out from the traits of their offspring.
In a large, out-crossing community, each of the individuals indicated by arrows is likely to be unrelated. Their genetic heritage is probably quite different from that of the person they marry. This makes it difficult to follow the inheritance of rare recessive alleles, where we have little data to identify those who carry them.
In a small, isolated community, the individuals indicated by arrows might well share genetic history with others on the family tree. Alleles that are rare in the population overall may well become homozygous with a moderate frequency in such communities. This may be problematical for the individuals involved, if such an allele causes medical problems. And yet...the family relationships make it easier (and therefore faster) to unravel the inheritance patterns of rare alleles, and even to identify the specific genes responsible for the medical conditions.
In the family tree shown above, white arrows indicate individuals who have married into the family. Their genetic history is unknown to us. The red arrow identifies the individual who brought a particular rare, recessive allele into the community--the allele indicated in the diagram with blue shading.
Now, consider the physician caring for the three siblings at the bottom of the diagram, indicated with blue arrows. These three share a rare medical condition. What is its origin? The family records indicate that the parents of these three siblings, their grandparents, their great-grandparents, and their great-great-grandparents seem to be from different families. It is only when we trace the family tree back to the great-great-great-grandparents that we find that they are sisters. We can trace the inheritance of the rare "blue" allele with our family tree, but the physician, in the real world, has only the medical condition and the distant relationship to work with. We do see, however, that the father of the three affected siblings had a relative with the same medical condition (indicated with the green arrow). This relative was his father's cousin--not a close relationship, but one that might suggest to the physician that the medical condition might have a genetic origin. Only a great deal of "genetic sleuthing" can reveal the true relationships--determining the complete family tree.
From looking at this pedigree, knowing only the medical condition, can you distinguish between a heritable genetic condition and a disease?
Most heritable genetic conditions in humans have been discovered in extended families in which many individuals share the condition. Researchers start with the family pedigree, such as we show here, because that's all the information we have at first. What follows is then a great deal of detective work, following additional generations, obtaining DNA samples for analysis, and investigation of the biochemical characteristics of the condition. Only after this work can we begin to link the genotypes of the family members (the alleles that they carry) to their phenotypes (the extent to which they display the heritble condition).
The tremendous importance of medical genetics in humans is countered by the complexities of our family pedigrees, and the fact that we typically marry individuals who are not closely related to us. Even for something as visible as hair color, we find that the "Rules of Inheritance" are easier to figure out when we use an animal model, and then come back and apply to our own families what we learned from the study of other species.
It is particularly striking that Gregor Mendel worked out the Rules of Inheritance--rules that apply to humans--using garden peas. Even plants provide a valid model for the analysis of genetic inheritance. The fundamental principles of genetic inheritance turn out to be the same in all species.