Aging
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This
overview of modern genetics is excerpted from the online book: The
Evolution of Aging http://www.azinet.com/aging/Aging_Book.html.
Our knowledge of the mechanics of genetics
has increased enormously since the
time of
Darwin
or even the time of Medawar
. This chapter is intended to provide only a brief summary of the aspects of
modern genetics that are relevant to discriminating between various theories of
evolution and theories of aging. (See a genetics textbook such as the excellent GENES
VIII by George Lewin for more on genetics.) Since evolution involves the
modification and propagation of heritable information that directs the
characteristics of organisms, an understanding of the mechanics of genetics is
critical to understanding evolution.
Early scientists thought that sexual reproduction involved transmission of a
miniature microscopic animal. The animal merely subsequently grew larger. But
what was the source of the miniature animal? Another theory had it that the
miniature animals were nested such that the outermost animal grew larger and
then transmitted the remaining nested microscopic animals during reproduction.
This scheme would apparently be limited in the total number of consecutive
reproductions and also did not explain why animals shared characteristics of
both parents.
By
Darwin
’s time, it was apparent that what was transmitted in reproduction was
primarily information that enabled the descendent organism to construct
itself according to a plan that was provided jointly by its parents. The
information was somehow stored in the organism during its life and then
transmitted to descendents during reproduction. Although early scientists
thought that events that happened during the life of an organism could affect
and modify the stored information in a structured way, this was subsequently
disproved.
So sexual reproduction involves the copying
and transmission of genetic information as well as the structured merging of information from two parents. Growth of
an organism involves reading
and interpreting the information and constructing an organism
according to the plan conveyed by the transmitted information. Finally, the
design of all organisms provides some mechanism for storing
the genetic information so that it is available for subsequent reproduction.
Darwin
’s theory tells us that species evolved from other species so it is obvious
that some mechanism must exist for modifying
genetic information.
Darwin
’s theory says that species could build upon and extend the characteristics of
ancestor species so that it is clear that the modifications are progressive and
cumulative. We now know that evolution on Earth has been progressing for about
four billion years. The mechanism that is being used by nature to copy and store
genetic information is apparently capable of such high fidelity that such a
progression is possible.
Analog
and Digital Data
Here we need to take a small detour to discuss the two ways in which information
can be stored and transmitted, namely analog form
and digital form. These two modes for
transmission, storage, and copying of information have very different
properties.
In
Edison
’s phonograph (1877), a diaphragm converted the pressure of sound in the air
into the displacement of a needle that then made tracks on a wax or tinfoil
cylinder. The displacement and path of the resulting track was continuously
variable in response to the sound pressure. The phonograph was an
instrument for storing and reproducing information in analog form. The
information was both accepted and returned as a serial sequential stream. The
information stored in such a recording could be copied to make thousands of
duplicate recordings that could be transmitted far and wide. AM and FM radio,
“analog” television, audio cassette tapes, and VHS video tapes are examples
of current analog data systems.
In contrast, Morse’s telegraph (1844) represented a serial digital communications system. Instead of being continuously
variable, the signal sent down a telegraph wire was binary
and had only two states, “mark” and “space”, known in communications
terms as symbols. The operator converted written characters into a
“code” consisting of long or short marks separated by spaces. Longer spaces
denoted the beginnings and ends of characters. Yet longer spaces denoted the
beginnings and ends of words. Currently, the Internet, CDs, DVDs, space
communications systems, and digital television are all examples of digital
communications systems.
One of the problems with analog communications is noise.
Since the signal is continuously variable, any disturbance introduces an error
or discrepancy from the original signal that cannot be removed. This is an
especially severe problem when consecutive copies of information are made.
Edison
could make thousands of copies of an original because each copy was a copy of
the original, that is, there was only one “generation”. If we needed to make
a copy of a copy of a copy of a copy the noise buildup would be very severe.
Each generation adds more noise.
In digital systems, noise is not as much of a problem. Because the
telegraph had only two symbols, disturbing noise could not cause an error unless
it was so great as to cause “mark” to be confused with “space”. For the
same reason digital data can be regenerated and noise removed. Copies of copies
are not as much of a problem with digital data. A copy of a CD, or DVD is
usually exactly as good as the original. Copies of copies can be made
indefinitely.
Some digital systems have more than two symbols. For example, English, a
serial digital communications system, has 27 primary symbols (counting space).
Any digital system can ultimately be reduced to binary digits
or bits.
That is, we could convert the 27 possible English symbols to 27 possible combinations
of five binary digits.
Here is an illustrative example of a digital communications system:
Suppose we had some automated weather stations and wanted to send a
digital message from each station to our central location several times per
hour. Suppose further that our system works by sequentially sending any of four
possible symbols denoted A, B, C, and D. We could devise a message format or code
as follows:
ssswwwvvvdd+tttthhhppp…
Symbols would be sent in order reading from left to right.
First, the station sends a three symbol synchronization
pattern sss. This is a known fixed pattern that allows the receiver
to determine the meanings of subsequent symbols. We could choose the value AAA
for the synchronization pattern. (In English, synchronization is performed by
spaces and punctuation characters.) We can follow this with three symbols (www)
denoting the weather station sending the message.
Next are three symbols giving the wind velocity. Since there are four
possible symbols (A,B,C,D), three symbols together have a total of 64 possible
values. We could convert the analog wind velocity to a number between 0 and 63
and then represent it with three symbols. AAA would correspond
to 0, AAB correspond to 1, and DDD correspond to 63. Next come two symbols
denoting wind direction. Two symbols have 16 possible values. AA could
correspond to N, AB to NNE, and so forth. Note that information is being lost in
the conversion between continuously variable analog form and digital form.
Although the actual wind direction might be anywhere between say North and
Northeast, the “analog to digital converter” is forced to pick one of the
allowed values. Presumably, if the actual direction is closer to North than
Northeast or Northwest it picks North. Next, we have a single symbol denoting
the sign of the temperature, (D denotes positive) followed by four symbols
denoting temperature. Since four symbols are used, the temperature can have 256
possible values allowing temperature to be conveyed more precisely. We then add
three symbols each for humidity and air pressure. The system does not care if
there are extra junk symbols preceding or following the message as long as they
do not duplicate a synchronization pattern. This is because the format or rules
for transmitting and receiving the data call for looking for the synchronization
pattern and then interpreting only the specified symbols based on their distance
from the synchronization pattern. Notice that all the messages have the same
organization and format. The information is represented by the specific digital
content, which varies from message to message.
One difficulty is apparent. If the temperature or some other parameter
had the value 0 (corresponding to symbols AAA) then the receiver might
synchronize at the wrong place in the symbol sequence causing all the data to be
misinterpreted. We could eliminate this problem by forbidding the value 0 in any
of the data sequences and digitizing all the temperatures and other parameters
to values starting at 1 instead of 0.
This simple system illustrates some of the properties of digital
communications systems.
Because there are only a finite number of symbols, all the data in a
digital system is ultimately limited in “precision”. Nothing is continuously
or indefinitely variable. The degree of variability is determined by the number
of different symbols possible (in this case four) and the number of symbols used
to convey a particular parameter. The code or format used must be known and
understood in advance at both the transmitting and receiving ends of the
communication.
The consequences of an error in a digital code vary enormously depending
on where in the format the error occurs. A single symbol error in the
synchronization pattern would cause the entire message to be missed. A single
symbol error in the “most significant” (leftmost) symbol of the temperature
is 64 times larger than a corresponding error in the least significant symbol.
An error resulting in insertion of an extra letter or deletion of a letter in a
message would result in misinterpretation of all the subsequent data in the
message. Insertion or deletion of letters between messages would have no effect
unless it created a new synchronization pattern.
In an analog system, errors (noise) tend to cause minor deviations from
the true value of a communicated parameter but all communications have errors.
In a digital system, error-free communication is much more likely, but errors
occasionally still happen. The consequences of a digital error tend to be more
severe. In our example message format there are 22 symbols. An error in which
one of the symbols was replaced by an incorrect symbol (a substitution
error) would cause a major change in reported value unless it occurred in the
least significant symbol of a parameter. There are only 5 least significant
symbols in our code so more than 75 percent of the possible errors would cause
major, even catastrophic, effect. An error in which an additional symbol was
inserted or an existing symbol was deleted would be catastrophic in nearly all
cases because the subsequent symbols would be misinterpreted.
In modern digital communications systems various methods have been
developed to detect and even correct errors. One obvious technique is
redundancy. We could send or store the same information three times and compare
the data on the receiving or retrieving end. If any of the copies did not agree
with the other two we would know it contained an error and discard it. Many more
sophisticated ways of ensuring error free transmission and storage of data are
in current use.
The reason for this detour is that the “genetic communications
system” is in fact a serial digital system and bears an eerie resemblance to
modern digital data systems. The
genetic system has four symbols, synchronization patterns, formats, redundancy,
error detection and many other properties of digital systems. This has
significant consequences for evolution theory and aging theory as will be
explained in detail.
At
Darwin
’s time, many thought (despite some rather obvious discrepancies) that
inheritance was an analog,
continuously variable, averaging process. It was thought that characteristics of
progeny tended to average out the characteristics of their parents.
Darwin
’s world was an analog world.
Darwin
had no reason to consider the digital concepts discussed above.
Gregor Mendel
(1822 – 1884) was an Augustinian
monk who conducted very extensive crossbreeding experiments with peas and other
plants. Mendel’s paper Experiments in Plant
Hybridization
(1865) was not widely noted until
much later and was unknown to
Darwin
. Mendel determined that some inherited characteristics were discrete or binary.
That is, there was a minimum unit of inheritance such that some characteristics
were either inherited by a given individual, or not, with no averaging or
intermediate possibility. Inheritance of traits was not continuously variable.
Mendel also noticed that some inherited characteristics were latent. Progeny could exhibit characteristics that were not
displayed by either of their parents but were
displayed by grandparents or other ancestors.
Watson
and Crick
in 1953 published their famous paper
A Structure for Deoxyribose Nucleic Acid
describing the basic mechanism (the “double helix
”) whereby genetic information is recorded, copied, and transmitted in all
living organisms. They shared the Nobel Prize in Medicine for 1962 with
co-discoverer Wilkins.
Serial
Digital Genetic Codes
As determined by Watson, Crick, and extended by many subsequent investigators,
the system used by nature to store, copy, and transmit genetic information is a
digital system. Genetic information is conveyed by the sequence
in which the organic compounds adenine, guanine, cytosine, and thymine are
strung together to make long molecules of DNA. These sequences then ultimately
determine all the inherited characteristics of the organism. In computer
parlance, this would be a serial digital code.
Because of the digital nature of the genetic code, some parts of genetic
sequences have been faithfully reproduced (ie consecutively copied) for billions
of years. As we have previously seen, an analog system would never be
capable of accommodating the very large number of consecutive duplications
involved in the evolution of life on Earth.
Since there are four possible nucleotides
, (A, G, C, and T for adenine, guanine, cytosine, and thymine), each nucleotide
(also referred to as a base, or base
pair) corresponds to two bits of information. We could translate A to
00, G to 01, T to 10, and C to 11 and then represent any amount of genetic code
as a binary number sequence. AGTTC
would then be 0001101011. The nucleotides are the symbols of the genetic code.
The Human Genome Project
in 2001 released a preliminary
report describing the genetic content (or genome)
for humans and determined that the human genome contains about 3.3 billion bases
of information. By early 2003 the sequence had been 99.9 percent determined. In
computer terms this is about 6.6 billion bits or 825 megabytes of data – small
enough to fit on your laptop computer’s hard disc. Approximately half of the
genome consists of repeat sequences
that are highly repetitive and therefore, according to information theory,
contain very little information. Some of the repeats are tandem
repeats that consist of sequential repetitions of a simple sequence (eg.
ATATATATAT…AT). A large amount of the remaining code has no obvious function.
Although the sequence has been determined, the actual specific functions of most
of the genetic code remain unknown.
Animal genetic code is transmitted in the form of contiguous,
sequential, DNA molecules called chromosomes
. Humans have 23 chromosomes. Mice have 20. Dogs have 39. Some plants have more
than 100. Small objects in the female egg cell called mitochondria
that are duplicated in subsequent cells transmit a small percentage of human
DNA.
Chromosomes have special sequences on either end called telomeres
(in humans, repeats of the sequence
TTAGGG). Another special sequence
more centrally located (position varies depending on the chromosome) is called
the centromere.
When a cell divides to form a second cell, the genetic information
content is duplicated in a process called mitosis.
The telomeres, centromeres, and other structural aspects of chromosomes are
known to be essential to the proper duplication of one (and only one) complete
set of chromosomes during cell division.
Almost every non-sex cell has two copies of the genome, (two sets of
chromosomes) one inherited from each parent. Sperm and egg cells only have one
copy.
Mice have a genome of about 3 billion bases (only 10 percent less than
humans).
Yeast has a genome of about 12 million bases, 6000 genes
on 16 chromosomes.
The bacteria e coli has a
genome of 5.6 million bases.
A major genetic curiosity, the microscopic amoeba (Amoeba
dubia) has 670 billion bases in its genome!
To further illustrate the information content, the upper and lower case
characters in the English alphabet (52 alphabetic characters, 10 numerical
digits, and space) could be represented in binary form using 6 bits per
character. The phrase “
Four score
and seven” would correspond to a binary string of 120 bits and could be
expressed in genetic code
using 60 bases. (This book contains
about 300,000 characters equivalent to 900,000 bases of genetic code.)
The probability of duplicating “
Four score
and seven” by random combination of bits (as might be done if you had
“enough monkeys and typewriters”) is one in 2120 or one in 1036.
It would take a very, very, large number of monkeys and typewriters a very long
time to randomly duplicate even this very short phrase! A single error might
result in “Four scBre and seven”. Several errors could look like “Fouw
scory and 8even”.
The reason for this diversion is that geneticists can trace descendency
at the species as well as the individual level. If you and any other living
thing share a significant sequence of code that is approximately the same then
you and the other organism must have had a common ancestor because the chances
of a random duplication are impossibly low. Not only can they determine if you
are related to your alleged children, they can determine if mice and men had a
common ancestor (yes, of course) and can even determine from the number of
errors that have crept into the genetic message approximately how long ago
humans and mice had a common ancestor (about 50 million years ago). (It is
possible for DNA in an organism to be, in effect, “cross-contaminated” with
DNA from another organism but this method is considered minor relative to direct
inheritance of DNA sequences.)
Errors
and Mutations
Errors
in copying genetic data are the source of the genetic changes that drive
evolution. Some errors, such as in a sequence which controls basic cell design,
or oxygen transport, or other crucial process, are almost always immediately
fatal and so are immediately “selected out” and do not propagate into the
genetic code of descendent organisms. This sort of sequence tends to be “well
conserved” after billions of years. Humans
share some sequences with yeast that both humans and yeast must have received
from a common ancestor. Other sequences that control “how much” (how long a
claw, how much fur, etc.) are the source of the variation
that drives natural selection. An
error in such a sequence could well only cause slight variation of a parameter
and only very mildly affect fitness. Finally some sequences (as much as 95
percent of the human genome) have no apparent biological purpose. Changes in
such a sequence generally have no effect on the organism and are not selected
against at all, thus freely propagating to future generations.
In modern electronic data systems, it is not unusual for errors to occur
more or less frequently depending on the pattern
of the data. Errors in both electronic and genetic systems can be caused by substitution
of an incorrect letter in a sequence and can also be caused by deletion
of a letter or insertion of an
extra letter.
In the genetic code
, which is all about pattern and sequence, it is not surprising that it is also
true that the chance for an error is pattern sensitive. For example, humans have
a genetic structure called a variable number
tandem repeat
(VNTR). Copying errors
(insertion/deletion errors) which change the length of these repeats are thought
to occur virtually every generation. (These are the sequences whose lengths are
compared in some types of genetic fingerprinting.) Another illustration of pattern
sensitivity are the restriction
enzymes. There are many
different enzymes which can cause strands of DNA to be physically broken at
points where a particular sequence exists. For example the enzyme sgf
I causes breaks where the pattern GCGATCGC is encountered.
In the genetic code, occasionally sequences are duplicated. Genes in the
duplicated sections can have subsequent copying errors that sometimes result in
new, useful genes. Presumably, this is the mechanism whereby a more complex and
longer genome can evolve from a simpler one. In human genetic code there is a
specific pattern of about 300 bases called the alu
element. Alu is repeated about 1 million times in the human genome and is
thought to have a significant role in affecting duplications, which in turn,
have a significant role in genetic diseases as well as in implementing evolution
of the genetic code. Alu elements represent about ten percent of human genetic
code, have no known biological function, and are often considered part of
“junk” DNA.
Genes
Genes
perform the actual control of physiological functions. Each chromosome can have
thousands of genes. The human genome contains approximately 30,000 genes but the
actual number is still unknown.
The structure of the sequence of information representing a gene as seen
reading sequentially along a chromosome typically includes regulatory regions at the beginning or end of the gene
sequence that determine when and where the gene is activated.
A gene is often thousands of bases in length. The coding
region
determines which protein will be
produced by the gene, that is, the sequence of amino acid molecules which will
be constructed to produce a particular protein molecule (often referred to as
the gene product). The properties
of a protein are determined not only by the number and type of the amino acid
molecules used in its construction but also by the particular sequence in which
the amino acids are assembled. The long protein molecules tend to “fold up”
in very complex ways depending on the particular sequence. This folding and
consequent shape of the molecule affects its properties. There are
therefore an essentially infinite number of possible different proteins. The
largest known human protein has 27,000 amino acids corresponding to 81,000 DNA
nucleotides.
A particular three-letter sequence, ATG, is the synchronization pattern
denoting the start of a coding sequence; other three letter sequences (known in
genetics parlance as codons)
denote particular amino acids to be sequenced into a protein and the end of a
coding sequence. Since there are 20 possible amino acids and 64 possible codons,
some errors in the third symbol of a codon have no effect. For example, CTA, CTG,
CTT, and CTC all code for Valine. This is a form of redundancy.
The regulatory regions
determine when, where, and how much
product will be produced. Some products are only produced in the liver; some are
produced only at certain times in an animal’s life, and so on. The regulation
involves the detection of chemical signals which can either enhance or inhibit
the gene’s expression. Although some genes produce
proteins used in the construction of tissue, many, probably a majority, produce
products that act as signals to activate or inhibit other genes thus allowing
the construction of a very complex regulatory logic framework.
If the regulatory region determines that a gene is activated, the cell
starts making copies of the genetic information in the coding region in the form
of small RNA molecules with sequences corresponding to the coding region. These messenger RNAs are used as templates by
the cell machinery that produces the proper protein molecules. (Sometimes the
RNA molecule itself is the gene product and performs some biological function
such acting as a signal to other genes.) The genetic code snippets will
preferentially adhere to a complementary string of code. “Gene chips”
carrying hundreds of samples of potential snippet complements can be used to
test for the presence of specific RNAs in a sample.
Using such gene chips, researchers can detect the presence of various
different RNAs in various tissues and thereby determine which genes were
activated. In connection with anti-aging research, detecting the differences in
gene activity between a caloric restricted animal and not, or between a progeria
victim, and not (see next chapter) could produce valuable clues regarding aging
mechanisms.
We can think of a specific “gene” as a message defining a product
that accomplishes a particular biological function. Since all multi-cell
organisms have a common basic cell design and function it should be no surprise
that there are genes that are common to all such organisms. As organisms become
more similar they share more commonality. It is estimated that 99 percent of
mouse genes have an equivalent human gene that produces a very similar product.
The organization of the genes in the genome
tends to be very different between even similar species. Mice have a different
number of chromosomes from humans and the equivalent genes are generally in a
different order on different chromosomes. Some genes are organized in groups or clusters that are conserved between mice
and humans.
Coding regions in the genes of more complex organisms have introns. Introns are portions of the coding regions that are spliced out and deleted from the code
during the creation and processing of an RNA. The deletion is caused by patterns
at the beginning and end of the intron that match in a particular way. Since the
introns are deleted, they have no known biological effect and are often
considered “junk” DNA. The remaining (functional) portions of a coding
region which are expressed in the RNA and subsequent protein are called exons. Exons are
thought to represent only about one percent of human DNA. Introns in humans
represent about five percent of DNA. Human genes have an average of five introns
and a maximum of 178 introns.
Genes are autonomous data units. They contain their own synchronization
patterns and operate somewhat independently. Junk DNA can therefore exist
between genes without disturbing their operation. The position (or locus) of a gene within a chromosome or on a particular
chromosome generally does not appear to affect the functional operation of the
gene. (In communications parlance such an autonomous unit would be referred to
as a packet.) (Some specific genes must be
located on the sex chromosomes in order to accomplish sex differences between
organisms.) If we inject a small loose string of DNA containing a single gene
into a cell, the cell will happily produce the gene’s protein product. This
approach is used in some forms of gene therapy. However, the loose strand of DNA
would not be duplicated during cell division because such duplication requires
the gene to be part of a chromosome. Methods for inserting new genes into
chromosomes have been developed and are used in genetic engineering. Such a gene
would be propagated during cell division and even possibly during reproduction
of the organism. While junk DNA and gene location do not affect the functioning
of genes they may well have significant evolutionary effects to be described.
All normal humans are thought to have the same genes, specifying the
same or nearly the same products, in the same order, on the same chromosomes.
Genetic differences between humans are expressed in the exact digital content of
their genes, generally minor differences such as single nucleotide
substitutions.
Mendelian genetics considers that some genes in a particular species can
have two different specific contents or alleles
such that two different results occur. Often one allele is represented by a gene
that is disabled and therefore produces no functional product, while the other
allele is represented by the functioning gene, a binary situation. In practice,
some genes can have more than one functioning state and a single gene can
therefore have more than two alleles.
A single substitution difference in a coding region exon (for example an
A could be replaced with a T) could cause a different protein or RNA product to
be produced, which in turn could have a significant effect but could also have a
mild or negligible effect. An error in the regulatory region or an error that
deletes the start codon or adds a stop codon could cause the gene to become
disabled and produce no product. Other errors could have more minor effects such
as changing the amount of product produced. Many of the more than 1000 known
human genetic diseases as well as most of the normal variations between
individuals are caused by such single letter differences in the genome.
In many cases of genetic disease, if one parent’s gene is disabled,
the other parent’s corresponding gene provides enough product so that
significant symptoms are avoided. The child and the first parent are carriers.
If the genes received from both parents are defective, then the child has the recessive
genetic disease. If one gene does
not provide enough product to avoid symptoms, or if an incorrect and deleterious
product is produced, then a defect in either parent’s gene can cause disease
symptoms in a dominant
genetic disease or other trait.
Many human genes appear to be duplicated, another form of redundancy.
So, by far the most likely possibility in a mutation is a single letter
error. It would appear to be ridiculously unlikely that an entire functioning
gene could be produced by a random mutation. The significance of this is covered
in the section on aging genes.
About half of the human genome consists of repeats of very short (2 –
5 bases) or relatively short (<300 bases) sequences. Since these repeats and
other “junk” DNA are between genes or in introns they have no apparent
effect on an organism’s function. However, they do have an apparent
evolutionary effect in that they influence mechanisms that cause segments of
code to be duplicated, copied to another part of the genome, or deleted. Introns
appear to have a similar evolutionary effect. The sections of expressed genetic
code (exons) between introns appear to correspond to “building blocks” or
“modules” that have been used by nature to produce a family of different
proteins each of which consists of one or more common modules added to a unique
sequence. Although the content and length of introns in a particular gene tends
to vary between species, the exons and the number of introns tend to be
conserved.
Meiosis
As mentioned, sex cells
have only one copy of the
chromosomes so that when a sperm and egg cell are united the resulting cell and
subsequent cells have a normal complement of two sets of chromosomes. In order
to do this, half of the genetic material is not used during the creation of a
sperm or egg cell. This process, called meiosis
, and other aspects of sexual reproduction
are extremely complicated as will be
summarized below. The reason for this detour is to demonstrate the enormous
difficulty nature has endured in order to produce the maximum possible variation
in organisms. These extremely
complex evolved mechanisms further validate
Darwin
’s theory of natural selection by means of natural variation and also lend
credibility to adaptive theories of aging as will be explained in Chapter 7.
In the process of meiosis, one chromosome from each set of two coming
from the two parents is randomly selected for transmission in the sperm or egg
cell. Humans have 23 different chromosomes (designated as numbers 1 through 22
in order of decreasing length and either “X” or “Y”). Note that the
complex selecting mechanism has to guarantee that exactly one of each set of two
chromosomes will be transmitted and that we do not possess three of chromosome 1
and none of chromosome 2, etc.
A random sort of human chromosomes would result in 223 or
8,388,608 different possible combinations. Each
parent performs such a random shuffle of the chromosomes received from their
parents in producing the sperm and egg cells. This would appear to guarantee
plenty of variation.
However, it was eventually determined through inheritance studies that
reality was actually yet more complicated. If only the chromosomes
were shuffled, then inheritance of a
gene on a chromosome would be tied to inheritance of another gene on the same
chromosome. If you inherited one gene from one parent, you would have to also
inherit the other gene from that same parent. (This would make it impossible for
nature to sort out the beneficial or adverse effects of different mutations on
the same chromosome and therefore drastically limit the process of evolution.)
At the same time if the two genes were on different chromosomes, inheriting one
would be completely independent of and not affect the chance of inheriting the
other because of the random chromosome shuffle.
(The plant traits that Mendel
used in his experiments happened to
be on different chromosomes. (Plants tend to have many chromosomes.)
If this had not been the case he would probably still be trying to make
sense of the inheritance patterns as explained below!)
Geneticists discovered that if traits were controlled by genes on
different chromosomes the inheritance pattern was, as predicted, completely
independent. However, if genes were on the same chromosomes the inheritance of
the respective traits ranged from almost independent (inheritance of one trait
was random relative to the other) to nearly totally dependent (inheritance of
one trait almost always meant inheritance of the other). They deduced that
during construction of sex cells (meiosis) one or more contiguous segments of a
parent’s chromosome is exchanged (crossed
over) with the other parent’s chromosome to make a new chromosome
that is a composite of the two parents. The length and position of the swapped
segment is almost random. As a result, the
probability of inheriting any two genes on a single chromosome from one parent
is proportional to the physical distance between the genes on the chromosome.
If two genes are physically close, then they almost always would be inherited
together, if physically distant, their inheritance would be almost independent.
Using this genetic distance principal and mind
numbingly tedious inheritance studies, geneticists have been able to determine
the approximate physical chromosome location of many genetic disease genes.
(This approach is very difficult if the disease or trait is the result of two or
more genes.)
In a further complexity, the swapping
process apparently only exchanges
sequences of code that are nearly identical at least near the ends of the cut
sections. This helps ensure that genes are only exchanged with corresponding
genes and the progeny does not end up with two of some genes and none of some
other genes or inherit partial genes or genes with insertion or deletion errors.
However, an error can occur if the end of a cut occurs at a place where two
identical code sequences (such as two alu elements) occur in a relatively short
stretch of code. The cut might exclude or duplicate the section of code between
the identical sections. It is thought that some genetic diseases are in fact
caused by these kinds of errors in the crossover process. This unequal
crossover mechanism is significant in supporting genome evolution.
Occasionally, humans inherit three copies of chromosome 21 instead of
the normal two copies. As a result, 50 percent more of some gene products is
made than normal. This in turn results in a genetic disease characterized by
mental retardation and physiological abnormalities known as Down syndrome
. Other chromosome abnormalities include inheriting less or more than two of any
chromosome, swapping of genetic material between different chromosomes, or
losing parts of chromosomes. Most such abnormalities cause fetal death or
degradation so severe that propagation in a wild population would be impossible.
However, the fact the Down syndrome is not immediately fatal despite duplication
of hundreds of genes illustrates that duplication of some genes might happen
without severe adverse consequences. Duplication of genes is part of the process
whereby organisms evolve more complexity.
Sexual
Reproduction
Animals have special X and Y chromosomes to help manage sexual reproduction
. Female humans have two X chromosomes
(which are paired and swapped during
meiosis like other chromosomes). Males have an X and a Y chromosome. Therefore,
progeny always inherit an X chromosome from their female parent and have a 50
percent chance of inheriting an X chromosome from their male parent thus
resulting in a 50 percent chance of being either male or female. In humans, the
X chromosome is larger and has more genes than the Y chromosome. The gene that
triggers “maleness” is on the Y chromosome.
One aspect of this arrangement puzzling to geneticists was how do
females avoid having something like Down syndrome
. Since females have two copies of chromosome X and males only have one copy,
females would appear to have 100 percent more of some gene products than males
(or males have 50 percent less than females). (I know that at this point, some
men and woman readers will be saying, “that explains a lot” about women or
men respectively.)
Eventually, it was determined that, in females, one (and only one) of
their two X chromosomes is randomly “inactivated” such that, functionally,
females only have one X chromosome. X inactivation
is another in a long list of evolved
complexities associated with sexual reproduction
.
At
least in higher animals, a process similar to X inactivation inactivates certain
genes as development proceeds. As stem cells differentiate into more specialized
cells, some genes are marked as inactivated (genetic imprinting) which partly
enables the capability for structural and functional differences in different
body cells. The inactivation state of genes is copied during mitosis. So
although almost all your cells have all your genes, in most cells some genes are
inactivated. This inactivation is removed during meiosis and also when cloning
animals from differentiated cells such as skin cells.
Polymorphism
and Variation
A polymorphism is a situation in which a
characteristic possessed by individuals in the normal population varies. If 90
percent of the flies have black eyes and 10 percent have red eyes, this would be
an eye-color polymorphism. “
Normal
” is often defined as meaning that at least one percent of the population has
the variation. At the genetic level, it is now estimated that normal humans
possess genetic codes that are as much as 99.9 percent identical. However, there
are an estimated 3 million places in the human genetic code where a single
letter is different in some individuals. In such a location, a letter might be
“A” in 85 percent of the people and “G” in the remaining 15 percent.
These “Single Nucleotide Polymorphisms” or SNPs represent and convey the
“normal variation” between humans. Presumably, the number of polymorphisms
would be much less if we considered only individuals in a particular race and
would be progressively still less if we considered only a particular ethnic
group, clan, tribe, or family. Extensive research is now under way to identify
which SNPs are associated with which identifiable characteristics and to
determine how SNPs vary between races, ethnic groups, and families.
If indeed there are 3 million SNPs, (some estimates are as high as 10
million), then there are 2 3,000,000 possible combinations of those
SNPs, a very, very large number of combinations. Every human is therefore unique
and expresses a different combination. At the same time, as explained earlier,
the probability of inheriting any part of the genetic code with some other part
depends on the physical distance (genetic distance) between the two segments on
a chromosome. SNPs that were close together on a single chromosome would tend to
be inherited together. SNPs that were very close together would tend to be
inherited as a unit that would tend not to be divided even after many
generations. SNPs that were far apart or were on different chromosomes would be
shuffled in every individual. Many SNPs are known to be clustered and their
inheritance is therefore complicated. These details regarding the inheritance of
variation are critical to theories of evolution such as the selfish gene theory.
A main purpose of this section was to demonstrate that, far from being a
fundamental property of life as was plausible in
Darwin
’s analog world, variation is implemented by a number of very complex evolved
biological mechanisms that were necessary to provide variation in the actual
genetic digital world. The variation is so extensive that in complex organisms,
every individual expresses a unique combination
of inherited characteristics. The details that have been revealed fairly
recently about the structure of genes, mechanics of inheritance, and the
mechanics of genetic diseases are critical to the more recent theories of aging
and cast increasing doubt on the traditional theories that were developed before
these details were available.
This brief overview does not begin to convey the complexity of genetics
. A typical, college level, genetics textbook is more than 3 inches thick and
only provides relatively superficial coverage of what we think we understand
about genetics. What we do not yet understand could obviously fill several or
even many additional books. Genetics is like a matryoshka
doll. Solving one puzzle often leads to yet another puzzle.
The Occam’s razor
principle teaches that if two
theories fit the facts, then the simplest theory is the most probably correct.
In genetics, and biology generally, there seems to be a “reverse Occam’s
razor principle” which goes something like: “No matter how complex a
biological process or system appears to be, in reality it is probably more
complicated.”
Biological
Plans and Schedules
Any major project involving the construction of anything, say a house, involves
plans and schedules. The plan
(in this context) describes the physical locations of various components. There
is a window here and a door there. Plans normally do not get too detailed. They
do not specify the position of every brick but merely specify that a wall of
certain dimensions is to be built of a certain type of bricks. The schedule specifies the time
sequence in which the components will be installed. Some tasks can be
performed in parallel. Other tasks can only be performed following the
performance of some other portion or portions of the work. We cannot install the
roof until the underlying structure is installed. We must install the roof
before installing materials that would be damaged by rain. More complex portions
of the work usually take longer to complete and involve more of these sequential
tasks. It is usually beneficial to optimize the schedule to result in finishing
the project as rapidly as possible to save time and therefore money.
The growth of a biological organism involves the same kind of processes
except that the plan and schedule are genetically transmitted such that an
organism constructs itself. Similarly to house construction, there is an obvious
competitive benefit to be gained from more rapid development to maturity. In
addition, in organism growth, complex structures such as eyes tend to start
development earlier. Finally, the genetic plan provides more detail for complex
structures. Presumably, much more genetic code is involved in the specification
of eyes and brain than large, simple, repetitive structures such as the gluteus maximus.
Although different cells contain the same genetic instructions,
different genes are activated in the growth and subsequent life of different
cells. This accounts for their physical and functional differences. One
mechanism whereby the different activations are implemented is a framework of
chemical signals. As an organism grows, cells produce an expanding array of
chemical signals that affect activation of genes in subsequent cells that then
form different structures and systems. Such signals can either enhance or
inhibit gene expression.
Enrico Coen, in his book The
Art of Genes, describes how the structure of a fruit fly is
determined by this process. In humans and higher animals, at least one
additional process, the progressive inactivation of certain genes as stem cells
differentiate, also helps determine which genes are activated in a particular
cell. The mechanics of this differential inactivation are not yet well
understood.
In this connection, we tend to think of chemical signals such as
hormones circulating throughout the body. However, depending on their
solubility, diffusion characteristics, and other attributes, signals can be very
local. Coen describes experiments in which transferring material from one part
of a fly embryo to another resulted in the development of two-headed embryos and
other structural abnormalities depending on the circumstances. Many signals are
internal to individual cells and are even local to particular locations within a
cell.
Even less well understood are the mechanics of biological scheduling. It
is clear that development of complex organisms involves complex scheduling
functions and that optimization of the schedule has an evolutionary benefit.
Even at the cell level, there are many processes that must occur in a particular
order. Chemical signals such as hormones and RNAs clearly play a role in
scheduling of animal growth. The completion of a task often results in
production of a chemical signal that activates genes to begin the next task and
inhibits the genes that performed the completed function. Presumably, the
scheduling aspects of an organism’s development evolved in parallel with its
structural and behavioral aspects.
The need for gene activation and deactivation and more specifically for
a scheduling system to handle sequential biological activities has implications
for aging theory. “Mature adult” would presumably be the last stage in the
life of a non-aging animal. There would be no need for the “schedule” to
extend beyond “mature adult”. We would therefore not expect to see hormone
levels change as a function of age beyond full maturity and the end of the
schedule. A mutation to a gene can clearly cause a problem at any one of the
points in the biological schedule where the mutated gene would have been
activated. A disabling mutation to a gene which is normally active in, say,
childhood development, would cause a problem when the person reached that stage
in life. But how could we have a mutation to a normal gene which only causes a
problem after the end of the schedule. By definition, there should not be any
genes that are only activated after
the end of the schedule. By definition, there should not be any way to activate
genes only after the end of the schedule. Mutations to a gene should cause
problems during the schedule but not after the end of the schedule. This would
appear to be a major problem for traditional theories of aging which depend on
the idea that random mutations exist which only cause a problem in older
individuals or that genes can exist that have beneficial properties in youth but
are adverse in older animals.
Chickens
and Eggs
It is apparent from the discussion of genetic mechanisms that many issues along
the lines of “which came first, chicken or egg” apply. It does not appear to
make any difference what three letter sequence “codes for” a particular
amino acid but the mechanism that reads the genetic code and assembles the amino
acids must have the same rules that were used to write the code. For the system
to work, the receiver of the message and the associated mechanism must have the
same understanding as to the meaning of the various codons as the transmitter.
(Some organisms have been found that have slightly different correspondence
between codon sequence and amino acid.)
The myriad chemical signals involved in gene regulation represent a
similar situation. Each signal that is sent has no meaning unless receivers for
that particular signal exist. The receivers have no function unless signals are
being sent. Evolution of such systems must take an extremely long time and be a
very incremental process. Thus, genetics further validates
Darwin
’s idea that evolution occurs incrementally.
We can see from the foregoing that there are at least five separate processes
involved in the evolutionary modification of the genetic code of organisms.
The first and most rapid process is the shuffling of the variable
elements (i.e. single nucleotide polymorphisms) of the code through crossover
and meiosis. Every individual animal represents a different combination of the
variable elements. We can observe variation by looking at a single generation.
In the second process, natural selection or selective breeding increases
or decreases the population density of specific variations. Eventually a
particular variable element allele could be eliminated from the population or
become universal. However, natural selection or selective breeding cannot alter the perhaps 99+ percent of the genetic code that
does not vary between individuals. Natural selection or selective breeding also cannot create variable code elements that
do not already exist. We can easily observe the effects of this second process
in breeding experiments or in observations of domesticated species.
In the third process, errors in copying code (mutations) introduce new
variable code elements in existing genes (e.g. single nucleotide substitutions).
Presumably, because of the digital nature of the genetic system, many such new
variations are sufficiently deleterious as to result in their being fairly
immediately selected out. Some have fitness effects that are initially either
positive, neutral, or sufficiently mildly negative so they avoid being selected
out and eventually spread in the population to become polymorphisms which can
participate in the second process. An error that causes a non-duplicated gene to
have an entirely different protein product would appear to be unlikely to
propagate even if it resulted in a potentially useful product because the
original function of the gene and its benefit would be lost. A simple mutation
such as a single letter substitution cannot alter a gene that does not already
exist and therefore is limited in the scope of the changes it could cause in the
design or behavior of an organism. In order to increase in complexity, an
organism would presumably need to have more
genes, not just changes to existing genes.
In the fourth process, entirely new genes are created by means of
copying errors in which entire genes are duplicated. The third process could
then differentially modify the two genes such that they produce different
proteins and thereby have more substantially different functions. In this way,
additional genetic functions can be produced.
In the fifth process, genes are moved, or transposed,
to different positions in the genome. Although such transposition does not
affect the gene’s function it does, because of the genetic distance principal,
alter the inheritance patterns of genes and thereby alter evolution.
Speciation appears to be more dependent on organization of the genome than on
content. It is clear that the mechanics of sexual reproduction including
chromosome pairing, meiosis, and gene crossover depend heavily on a very high
degree of similarity in the genetic organization (such as the number of
chromosomes and order of genes on chromosomes) of the parents. Wild animals are
observed that are nearly identical but nevertheless belong to different species.
Domestic animals (e.g. dogs) are observed to be drastically different but
nevertheless belong to the same species. Speciation has a dramatic effect on the
process of evolution because it prevents transmission of genetic characteristics
to coexisting species.
Every species presumably inherits the vast majority of its genes from
its ancestor species, some from very distant ancestors. Most of the genetic code
therefore has a longer lifetime than the lifetime of any individual species.
Here are some examples of the potential complex interactions in these processes
that are disclosed by our current fragmentary understanding of genetics.
Although alu elements have no known biological function, they could have
a significant effect on the evolution of genetic code. The presence of alu
elements in a particular region of genetic code increases the chance for
subsequent duplications or deletions of code sequences (during meiosis and
crossover) in that region and therefore affects the fourth process.
Although introns in gene coding regions have no known biological
function, the presence of introns could also affect the probability of and
process of duplication. An alu within
an intron could affect the probability that part
of a coding region might be duplicated or deleted, thus affecting the fourth
process.
In addition to alu elements there are many other repeat patterns that
could have similar effects on evolution of the genetic code.
We have to believe that the survival value of most variations are
dependent on other variations. For example, a larger eyeball might be beneficial
but only if accompanied by a larger eye socket. Now presumably there are genes
that affect the size of the whole animal, there are genes that affect the size
of the head relative to the rest of the animal, and there are genes that affect
the size of the eyeball relative to the rest of the head. Similarly, physical
characteristics of organisms must be matched by appropriate behaviors and
behaviors must be matched by appropriate neurological systems. It is clear that
evolution would be assisted if inheritance of certain genes was associated with
inheritance of certain other genes such that, for example, eye size tended to be
associated with eye socket size. We know that the degree of such association
depends on the relative physical location of the genes in the genetic code of a
chromosome. It “boggles the mind” to contemplate how long it could take to
achieve these kinds of associations through the process of gene copying and
transposition. Presumably, many such associations as well as their underlying
genes are inherited from ancestor species and have long lifetimes relative to a
“species lifetime”.
Because mutations in junk DNA presumably have no biological effect, such
mutations can propagate easily through a population. The presence of these
mutations could then affect the probability of subsequent mutations through
various forms of “pattern sensitivity” and processes such as described above
and thereby have significant long-term effect on the evolution of that
species’ genetic code.
It is estimated that only about 1 percent of human DNA is in the form of
gene exons. If we include in “functional DNA” all the regulatory regions,
critical leading and trailing patterns in introns that cause them to be introns,
the patterns in telomeres and centromeres that cause them to function, and all
the other DNA that seems to have some fitness effect, the total functional DNA
is probably less than 5 percent of the total genome.
Suppose we were to rearrange the genome of a mouse. We could take the same mouse
genes (excepting the sex chromosomes) and place them in different positions on
different chromosomes. We could even equip our new mouse with a different number
of chromosomes. Because the new mouse has the same genes, the mice in a
population of new mice should be physically indistinguishable from old mice.
They should have the same fitness as old mice. The only difference is the order
in which the genes are sequenced in their chromosomes.
We can make some more changes. We could add introns to some genes and
delete introns in other genes. We can change the specific internal sequences of
introns. We can add, or delete, or change the content, of other junk DNA. As far
as is now known, none of these changes would affect the appearance, behavior, or
fitness of the new mice relative to the old mice.
However, it is clear that we might be drastically altering the ability
of the new mouse to adapt and evolve. Since genes are in a different order,
genes that formerly tended to be inherited as a group because of short genetic
distance would now be independent. Other genes formerly on different chromosomes
could now be in clusters. Protein “modules” formerly available because of
intron structure would no longer be available. Although the new mouse is
physically and functionally identical to the old mouse, the mechanics of
evolution available to the new mouse would appear to be significantly different.
Because of the major differences in genome organization, the new mice would be
unable to interbreed with old mice. The new mice would be members of a
different, though physically identical, species.
Because of the large differences in genome organization between similar
species (e.g. mammals) it is clear that the organization
of the genome evolves. This evolution must necessarily be extremely
“incremental” (more “tiny steps”) in order to maintain the ability of
individual members to interbreed.
This entire scenario appears to be incompatible with classical Darwinism
as follows.
Darwin
’s theory holds that mutations that are beneficial to an organism increase its
fitness and mutations that are adverse decrease its fitness. Mutations with
positive or zero fitness impact can eventually become widely distributed.
Period. In the above discussion we have identified a whole family of different
types of mutational changes which have no immediate fitness effect but which
plausibly benefit or detract from the ability of the organism to subsequently adapt through evolution by reducing or
increasing the probability that certain types of subsequent mutation can occur.
In effect, these mutations affect the future
of the organism in terms of the descendent species it might produce or the
“evolution of its species”. Although such mutations, either beneficial or
adverse, could, (since they are fitness neutral), spread through the population
of a species and could be transmitted to any descendent species, they cannot
spread to co-existing species. This suggests that “survival of the species”,
that is, species that produce descendent species or which “evolve”, as
opposed to becoming static or extinct could play a much more important role
relative to “survival of the fittest individual” than contemplated by
classical Darwinism.
The purpose of this chapter has been to illustrate the complexity that has
appeared as we discovered more about the mechanisms whereby evolution of genetic
codes actually occurs.
Darwin
’s analog world is very simple when compared to the digital reality. Breeding
experiments and heredity studies are generally confined to exploring variation
and natural selection. Variation and natural selection are essentially the
easily observable “tip of the iceberg” regarding the mechanics of genetic
code evolution. The time scales of these different processes differ enormously.
The selection of a trait that was represented in variations could take a
relatively few generations. Other traits, produced or affected by non-variable
parts of the genome code could be conserved for millions or billions of years.
Details of the mechanics of the third, fourth, and fifth processes could explain
why
Darwin
’s theory does not work for aging and other troublesome animal
characteristics. Specifically, it appears that evolution could involve much
longer times and more complex processes than contemplated by orthodox Darwinism
and that therefore the importance of “individual” fitness could be less than
considered by
Darwin
. At the same time, knowledge of these complex processes supports
Darwin
’s determination that sudden massive mutations were unlikely to have a
significant role in evolution.
Copyright © 2004 Theodore C. Goldsmith