a. The history of genetics
At the end of the last ice age, roughly 10,000 B.C.E., humans began intensively cultivating plants into crops and domesticating animals. Agriculture and livestock breeding selected a modest set of desirable traits such as caloric content, palatability and medicinal value, while animal husbandry improved strength, stamina, appearance and behavioral profile in dogs, cats and additional quadrupeds for purposes such as companionship, packing, herding, guarding, tracking, retrieving and aesthetic form. Since this selective breeding took place over many millennia, general trends were not examined with any comprehensiveness or much integration until life science commitments began to mature in the 19th century, at which time biology expanded into a discipline with the breadth of systematic observation and a scientific methodology sufficient to approach organic phenomena as well-defined mechanisms in the context of progressing generalization, what had come to be called ‘theory’. Breeding of plants and animals became much more nuanced, trait variety proliferated at an increasing rate, some of the same phenomena of diversification were noted as happening spontaneously in natural environments via biological evolution, and interest in applying controlled experimentation to the investigation of heredity came into being.
The monk Gregor Mendel was the most well-organized early researcher into heredity, putting together experiments at his monastery involving thousands of organisms to test intuitions. His experimental subject of choice was the pea plant; he controlled cross-fertilization and compiled data to establish statistical trends in select traits over multiple generations. What he proved was that offspring in this species were not a perfect medium between their parents, but produced either the chosen trait of one parent or the other in a fixed ratio. For instance, tall pea plants and short pea plants did not result in middle sized pea plants but either tall or short offspring, and pea plants with purple flowers and those with white did not engender offspring with pink flowers but instead either purple or white.
Furthermore, in these two cases one trait was dominant (tall and purple independently), occurring more often in mixed trait breeding, and one recessive (short and white independently), surfacing less often. The ratio of dominant to recessive in the descendant generation of pure populations in which tall and short or purple and white had been equally represented was almost exactly 75% to 25% in a sample size of thousands. Breeding pure or ‘homozygous’ dominant populations produced 100% dominant, and breeding only homozygous recessive plants produced 100% recessive. From this it was apparent that both height and flower color in Mendel’s pea species are determined by two constituents geneticists later termed ‘alleles’, one from each parent, in which only the dominant is expressed in heterozygous offspring, but the recessive allele tags along in heterozygous reproduction and can appear in small proportion from breeding of the second generation. Thus, to Mendel is attributed our modern concept of the gene, a unit of heredity with replicative outcomes that are often predictable in exactitude from traits of parents, and not always in the way one would have expected from the bare notion of dyadic sexual combination.
Meanwhile, invention and refinement of the microscope had opened up a whole new miniature world for scrutiny by biologists, and it became clear from an accumulating collection of viewings that all lifeforms seem to be composed of units called ‘cells’ enclosed by a membrane, with internal features termed ‘organelles’. The witnessing of common cell division — ‘mitosis’ — revealed the presence of ‘chromosomes’ that thicken and become visible in the center of the cell during this process, featuring as the most prominent duplicated structure of new cell genesis, which suggested a core functional role. Chromosomes were soon found to reside in the nucleus under typical conditions, which by all indications seemed to be a likely control center sequestered from the rest of the cell. Sex cells or ‘gametes’ were also observed, and each egg and sperm from female and male respectively were shown to harbor half the number of chromosomes in a normal cell, which upon fusion form a fertilized whole cell from which the rest of the organism develops. Chromosomes were manifestly central to heredity as well as the locus of growth at the molecular level, and the race was on to determine their composition and means of functioning.
Science discovered in the first half of the 20th century that chromosome structure is based around a molecule called DNA (deoxyribonucleic acid) wrapped up as a multilayered winding of its long, stringy structure into a fibrous bundle, the behavior of which was still a mystery. It was clear that DNA is composed of a small set of molecular parts likely existing in a highly organized, recursive pattern, but the exact arrangement was not easy to discern. Multiple models were proposed and uncertainty was the rule until the 1950’s when researchers James Watson and Francis Crick solved the riddle, putting forward the correct orientation of subunits that also gave significant clues as to what a gene is biochemically.
b. DNA and RNA
DNA has a double helix shape, made of two lengthy strands extending in a corkscrew pattern, held together by comparatively weak bonds between medial molecules. The laterally located backbone of each strand consists of deoxyribose, a pentagonal (five carbon) sugar, connected to a single phosphate-based molecule, with this dual-faceted outer unit repeating at regular intervals. The internal bonds of DNA are comprised of four types of nucleotide base, with each single base fastened to a single sugar-phosphate unit. There are two base pairs, Adenine (A) bonding with Thymine (T), and Cytosine © with Guanine (G). The sequence of nucleotides contains the genetic code, with these rows, consisting of up to hundreds of millions of base pairs in a single human chromosome, regulating the production of proteins that anchor all the biochemical pathways and constructions of a cell.
The basic unit of the genetic code is a ‘codon’ composed of three successive bases that give instruction to manipulate a particular amino acid, which are the fundamental building blocks of proteins. All eukaryotic (multi-celled) life forms, evidently descendants from a single set of ancestral species by virtue of the following commonality, use the same 20 amino acids coded by 61 codons, with the total 64 possible being filled out by three ‘stop codons’ signaling termination of a ‘gene’ or protein-generating sequence; one of the codons is a ‘start codon’ causing every protein to begin with the same amino acid. The total of only four bases minimizes mutational inaccuracies that would emerge from excessive complexity while at the same time providing a template for substantial variability and new traits at a sufficient rate for adaptation to changing environments. Redundancy of multiple codons instructing for the same amino acid further mitigates impact of mutational processes, as these transformations avoid being catastrophic to the workings of a cell by utterly reconstituting proteins, with their intricate foldings and combinatorial properties, each time a codon changes.
A molecule related to DNA called RNA (ribonucleic acid, having an extra oxygen atom in each ribose sugar of its backbone) is also instrumental to the workings of the genetic code. It is a single strand with Uracil (U) substituted for Cytosine (C) that blueprints amino acid sequences with the same codon pattern as DNA. Its main role is as a messenger molecule transmitting substance of the code out of the nucleus as a copy of DNA’s structure to make possible processes of protein synthesis throughout the cell. It also participates in transporting amino acids to proper sites for bonding into proteins, and also in catalyzing protein synthesis as part of the structure of the ‘ribosome’, an enzymatic hybrid of RNA and protein segments. DNA and RNA initiate all cellular biochemistry by dictating molecular structure, and together with feedback loops that regulate their operations provide the patterns and distribution of genetic information, a phenomenon the following theoretical mechanisms model with superb reliability, allowing scientists to actually engineer genetic code and its expression as technology for the sake of novel applications.
c. The molecular mechanisms of genetics
Genes are sections of the genetic code up to many thousands of base pairs long, each providing instructions for synthesis of a particular protein. Gene expression is regulated by epigenetic processes such as methylation — attaching of CH3 groups to the sugar-phosphate backbone — and targeted unwinding of the DNA molecule for exposure to dissolved substances in the nucleus, initiating diffusions and biochemical pathways which lead to cytoplasmic solution outside the nucleus, the membranous surface of a cell with its communicative markers, and ultimately levels of chemicals such as hormones, also anatomical surfaces, and the environment external to an organism. Genes are organized into larger units, like a biochemical paragraph of grammatical sentences, the hybrid expression of which affects characteristics of macroscopic body parts and functions, such as limb shape, skeletal structure or genitalia. The activation or suppression of genes at different developmental stages and under varying environmental conditions plays a pivotal role in growth as well as adjustment to adaptive demands in the short-term that occur cyclically (such as climate fluctuations) and to changes in physiological chemistry. There is much more to be learned about interaction of DNA with natural selection and the chemistry of cells; we have barely scratched the surface.
Translation of a gene encoded as base sequences of DNA into protein begins when an enzyme called reverse transcriptase is prompted to unzip the relatively weak bonds of base pairs and travel down one strand of the DNA molecule. As it proceeds it creates a single-stranded RNA molecule (with U instead of C) called mRNA (messenger RNA) that is a copy of the opposite strand’s code. When this enzyme reaches the end of the gene, a stop codon, it disengages and releases the mRNA molecule to nucleic solution. Proofreading functions do occur to minimize errors, but occasionally the wrong base will be substituted in mRNA, which is a source of mutation, altering protein coding. These subtle mutational events can be magnified to much effect, transforming the internal environment of a cell in major ways, for reasons to be described next.
Once the mRNA molecule has been completed, it leaves the nucleus and enters the cytoplasm where its sequence of bases is replicated prolifically by the enzyme RNA polymerase. This enzymatic process has no proofreading built in, so translation errors abound and a whole host of even further modified code is constantly being generated. Another RNA molecule called tRNA (transfer RNA) with an anticodon — opposites of the mRNA codons — connected to some additional molecular material bonds to its specific amino acid in reactions catalyzed by enzymes. Once tRNA and mRNA converge on a ribosome, enzymes clamp the tRNA molecule to the corresponding codon of the mRNA strand and the ribosome munches the mRNA lengthwise, in the process bonding amino acids in specified sequence and emitting a fully formed chain — a protein — which then folds into a unique three dimensional configuration produced by attractions between its amino acids, combining with other substances such as additional proteins to assume its function in the cell, as a membrane-bound identification marker, enzyme, or structural and motile support.
Thus the cell is like a minute ecosystem with carnivorous ribosomes metabolizing mRNA prey in cooperative hunting with enzymes, fashioning proteins that participate in cellular processes including gene expression, and through a complex, circuitous route no doubt contributing anew to the lifecycle of the ribosome population and continual, collective renewal of all cellular materials. This ecosystem is characterized by extremely efficient circulation of energy and retention of matter in which even byproducts (proteins and post-reaction, disassembled molecular components) are eventually recycled, furthering sustainment of the whole.
This is startlingly reminiscent of humanity’s cultural sphere, an increasingly streamlined cycling of resources within our growingly conservation-conscious, behavioral economy of joint finance. The modus operandi of a living cell is seamless function that far surpasses the efficiency of any human coercion, with each cellular unit of production in some measure serving its own as well as the greater interest. With human ethical standards, self-imposed restraint, language of practically infinite generative potential, reasoned collaboration and creative spontaneity, our civilized social systems ten thousand years in the making are perhaps capable of even greater functional and evolutionary potency than the cellular organisms which took billions of years of naturalistic trial and error to engineer. Anyways, back to genetics.
When a cell divides in two during tissue growth in a process called mitosis, chromosomes gather in a row down the middle of the cell. An enzyme called DNA polymerase unzips the DNA molecules, of which there are 46 in humans, and catalyzes formation of a full copy. Less often than with RNA because of proofreading, copy errors occur and result in new base sequences that change genes in the DNA code. The original code with occasionally mutated copying is divided into genetically homologous (nearly identical) portions and dragged to opposite sides of the cell by cytoskeletal fibers. The cell pinches in two down its middle, forming adjacent cells.
In human meiosis, a gamete is produced by further division into two cells with 23 chromosomes each, developing into egg and sperm. During fertilization, two gametes, one from each parent, combine to provide the full complement of chromosomes, a phenomenon that increases potential for inherited variability in offspring, as each meiosis-generated gamete ends up slightly different and sexual reproduction frequently combines gametes of divergent lineages with separate mutational and adaptive histories. When sexual recombination can no longer occur between sex cells of mutating populations, a ‘speciation event’ results and divergence of these groups usually accelerates, the species designation not being absolute as behavior and physiological chemistry contribute as much as genetic possibility. Physical separation of a species’ populations tends to increase their discrepancies by genetic drift, and introduction of a species to a new ecological niche often reinforces this trend because of selection pressures imposed on phenotypes — outward expressions of the genetic code — to mutate into alternative forms, enabling organisms to persist as environments change.
d. Phenotypes from genotypes in humans
The human genome is made up of more than 20,000 genes, each coding for a specific protein. The function of proteins is being widely researched as well as the way genes interact. There is much variety, as some traits exist on a spectrum and involve large numbers of genes, while some are simple with a very limited quantity of instantiations. Some phenotypes are as old as the human race itself, some even older, some have been highly selected by environments, some are deleterious, some common and some relatively rare, some nearly unselected and so almost incidental, some specific to a particular stage of life, some expressed in a proportion of all our species’ individuals independent of any particular line of human descent, and all kinds of permutations within these categories. A few types of traits and some examples will be addressed in what follows.
There are human traits as simple or nearly as simple as Mendel’s pea plants. One example is earlobes, with the detached kind being a dominant trait and attached being recessive, alleles located on only a single gene. Blond and red hair are usually recessive to black or brown, though exceptions do occur for reasons not fully understood, and more than one gene is of course involved. Green eyes are a dominant trait; when combined with codominant brown the resulting color is hazel, and blue is recessive to both. Though blue eyes are usually attributed to fair-skinned Caucasians, this trait is actually older than pale skin color and occurs occasionally in Middle Eastern and African individuals with no European ancestors.
Each cell has a pair of sex chromosomes responsible for many gender specific traits and maturation characteristics; males typically have an X and Y chromosome while females have two X’s, though in rare cases males can have two X chromosomes with no apparent abnormalities. Additional traits besides sex characteristics reside on these chromosomes and are considered ‘sex-linked’. An instance is a rare form of color blindness: it afflicts men more frequently than women because a normal copy on either X chromosome provides ordinary vision, but of course men have only one X so only one defective copy produces the disorder. Rarely, an extra chromosome is inherited, bringing the total to 47; this results in Down Syndrome, a condition that severely and negatively affects cognitive and physical abilities as well as lifespan.
Some genetic disorders such as Huntington’s disease are dominant traits but so detrimental that they remain rare, while others such as sickle-cell anemia are recessive. In this form of anemia, which is most common to Africans, a single base mutation (substitution of T for A) causes inclusion of the incorrect amino acid, valine, in B-globin molecules responsible for the shape of red blood cells. This gives these cells an elongated crescent form instead of the normal flattened sphere, reducing their ability to carry oxygen, which frequently causes disability and even premature death. However, the trait can have intermediate forms that allow for normal or nearly normal functionality while conferring resistance to malaria, accounting for its not unusual presence in those with ancestors from sub-Saharan Africa where malaria incidence is eons old and most prevalent.
Some traits such as the ability to metabolize carbohydrates reside within a simple spectrum; there are six genes involved in their digestion. A higher number of these genes confers greater ability to digest, with different parts of the world having differing amounts. Generally, the more ancient and sustained dependence on a carbohydrate diet has been for a region, the more contributing genes its ancestral ethnic groups have, up to six for Western Europeans and as few as two for some parts of Africa that relied more on herds with their lower carb animal products.
Sometimes the same trait has emerged in variable ways at different times; this is the case with lactase production, the enzyme that digests lactose sugar, an ingredient in milk. All humans begin life with lactase necessary to metabolize breast milk, but some lineages lose this as early as childhood. It is the case with East Asian individuals, who can experience severe indigestion from milk, but many of those with European ancestry retain lactase production into adulthood if milk products are not eliminated at some point from their diet. Middle Easterners have a different gene for producing lactase, and East Africans have bacteria in their gut that provide them with lactase, though the capability is not present in their genetic code. All of this results in a complex contour of lactose intolerance across the world population.
Some traits are quite new, resulting from recent evolution. The pale skin of Northern and Western Europeans is the best example. Until around 5,000 B.C.E. tinted skin was the rule as a consequence of life in tropical latitudes, where Homo sapiens and their ancestral hominin species lived off and on for millions of years. Substantial exposure to intense UV radiation near the equator can denature vitamin B9 circulating in blood vessels close to the skin surface, which in fair-skinned pregnant women sometimes causes birth defects such as abnormal brain development during the first trimester. Dark skin absorbs and deflects UV radiation, preventing it from penetrating deeply into tissue and protecting the fetus. However, sunlight absorption is what stimulates the human body to produce vitamin D necessary in calcium utilization, especially important for bone health, and UV exposure is scarcer and less intense during winter at higher latitudes where the slanted angle of sunlight causes impedance of the sun’s rays by the atmosphere and heavy clothing must be worn to ward off cold weather.
Because ethnic groups such as Mongolians and Tibetans have historically lived off domesticated animals, which is a diet relatively rich in vitamin D, they have not completely lost their darkish skin shade, and more southerly East Asians with rice or wheat-based diets less rich in vitamin D but with greater sun exposure due to closer proximity to the equator have experienced skin lightening in roughly the same measure. However, around 6,000 B.C.E. high latitude Europe transitioned from hunting to reliance on agricultural cereals, which is a diet very low in vitamin D; archaeology reveals that this resulted in widespread rickets, a disorder with symptoms such as brittle bones and bowed legs. It is estimated that about 1,000 years later a mutation of one base in a single gene resulted in pale skin, greatly increasing UV absorption and vitamin D production, so advantageous that it drifted the Caucasian population towards a lighter shade. It has been shown that this is the same gene causing a color change in zebra fish from striped to pale gold, demonstrating how genes of variable expression can nevertheless retain a general function: different pigmentation but the same role in relation to a category of phenotype.
First language acquisition in humans is a trait tied to a particular stage of development with a narrow window of expression. The rapidity with which infants and toddlers learn language is tied to the FOXP2 gene; by age five the effect of this gene has waned and mastering a new language becomes more difficult. After the critical period, children exposed to speech for the first time never acquire fluency, and for its duration multilingualism and native accent are easier to achieve. Brains of the very young seem predisposed by temporarily hardwired structure for the equivalent of language learning genius, a curious reality considering the immaturity of their minds. Mental resources are allocated much differently early in life than as an adult.
A genetic disposition exists for most individuals to be born with primary language centers in the left hemisphere of the brain, but in rare cases these areas are in the right hemisphere or both. This seems to be independent of ethnic or even family background, with the three profiles distributed in equal relative percentages throughout the world’s populations, evidence that variation can be no less systematic despite any latency, but often with a complexity that simplistic notions of heredity fail to account for. Traits can have the function of dominance or recessiveness in intricate, uncommon or difficult to predict ways.
While some of these genetic phenomena have been teased apart, coaxed into revealing their secrets, phenotypes in general result from a vast network of interrelated protein structures and functions that are only beginning to be understood. As research advances, comprehension of traits as mechanism will deepen and a vast vista of potential medicine and technology will become visible within the scope of knowledge, a future of ascending power and systemic risk; the stakes will be high and already are.