16
2 Nucleic Acids and Nuclear Proteins
supported both theoretically and statistically.
Computer simulation shows that in random
sequences of the four bases, a stop codon appears
after a maximum of 600 bp, and longer sequences
can be obtained only by excision of the region of
the stop codon and splicing of the resulting fragments; this coincides with the fact that only genes
of less than 600 bp have no introns [392]. If one
assumes a length of 20 kb for the primordial
nucleic acid molecule of the first organisms, then
a stop codon-free sequence (ORP) of 550 bp or
more would be expected in a maximum of 4.6 %
of all molecules; according to this, the excess of
non-coding sequences found today in most eukaryotes represents the original situation [318]. The
correspondence between exon and domain
boundaries, used as an argument for the associative origin of introns, does not apply to all proteins; furthermore, even homologous genes do not
always have the same number or location of
introns. Thus, the origin of introns through the
insertion of transposable sequences is by no
means excluded; perhaps the two mechanisms
exist side-by-side.
2.2 Multiple Genes and Pseudo genes
Many genes occur in the haploid genome in several, often very many, more or less identical
copies. This was already postulated two decades
ago because it was noted that there are many
cases where different proteins (globin isoenzymes)
with the same or a similar function exist in the
same individual. Today, one can detect all the
similar sequences in the genome by hybridization
with a DNA probe. Such experiments have made
it clear that there are further copies of almost all
genes somewhere in the genome, although in
many cases these may be non-functional. Multigene families make biological sense in two ways.
1. Dose repetition: In the biosynthesis of almost
all proteins, one gene is sufficient for a high
rate of synthesis because of the two amplifying
effects of transcription and translation. In the
formation of different RNA types, however,
including the 5S rRNA and the different
tRNAs, the second amplifying step is missing.
Many identical genes are required in this case
to satisfy requirements. The only example of
dose repetition of a protein-coding gene is that
of the histones, which must be produced in a
short period during the cell cycle in an amount
similar to that of the DNA. Here again, the
amplifying effect of protein biosynthesis is
insufficient. Only gene duplication or multiplication in the germline is appropriate, i.e. a
process of molecular evolution that affects all
the cells of an animal. The multiplication of the
genome or of single genes can also be limited
to particular somatic cells. This also serves to
cover increased requirements for gene products but it is a process of individual biochemical adaptation and will be dealt with elsewhere
(p.27).
2. Variant repetition: When multiple genes produced by gene amplification develop independently in evolution (diversification), there arises a family of related but significantly different gene products that may be adapted to various conditions in different cell types or in different developmental stages. This book contains many such examples.
Multiple genes arise through gene duplication,
the genetic mechanism of which is most likely
unequal crossing-over. The duplicated genes are
at first arranged one after the other (a tandem
cluster); the genes of a family can also be spread
throughout the genome (dispersed genes); and
finally, there are mUlti-gene families with most of
the members together in one or more clusters and
single copies (orphons) at other positions in the
genome. This phenomenon was discovered in
1981 in the histone genes of the sea urchin Lytechinus pictus, where more than 50 orphons have
been found, but is apparently quite widespread.
In cases of dose repetition, the genes of a gene
cluster are generally regulated together and,
through particular evolutionary mechanisms
(horizontal or concerted evolution), remain similar in sequence (homogeneous). Neither of these
is valid for cases of variant repetition. Orphons
are excluded from horizontal evolution and,
therefore, show great diversification.
In all mUlti-gene families there are probably
members that are not transcribed because of the
presence of some sort of defect. Such genes are
rather misleadingly termed pseudogenes. The
name was coined in 1977 by Jacq, who discovered
the first such gene within the 5S rRNA genes of
the clawed frog, Xenopus laevis. Many pseudogenes are now recognized, e.g. in the gene families
of the globins, the immunoglobulins and the
tubulins of various mammals, cytochrome c of
rats, actin and metallothionein of man, and the
cuticula proteins of Drosophila. In some gene
families, the number of pseudogenes greatly
2 Nucleic Acids and Nuclear Proteins
supported both theoretically and statistically.
Computer simulation shows that in random
sequences of the four bases, a stop codon appears
after a maximum of 600 bp, and longer sequences
can be obtained only by excision of the region of
the stop codon and splicing of the resulting fragments; this coincides with the fact that only genes
of less than 600 bp have no introns [392]. If one
assumes a length of 20 kb for the primordial
nucleic acid molecule of the first organisms, then
a stop codon-free sequence (ORP) of 550 bp or
more would be expected in a maximum of 4.6 %
of all molecules; according to this, the excess of
non-coding sequences found today in most eukaryotes represents the original situation [318]. The
correspondence between exon and domain
boundaries, used as an argument for the associative origin of introns, does not apply to all proteins; furthermore, even homologous genes do not
always have the same number or location of
introns. Thus, the origin of introns through the
insertion of transposable sequences is by no
means excluded; perhaps the two mechanisms
exist side-by-side.
2.2 Multiple Genes and Pseudo genes
Many genes occur in the haploid genome in several, often very many, more or less identical
copies. This was already postulated two decades
ago because it was noted that there are many
cases where different proteins (globin isoenzymes)
with the same or a similar function exist in the
same individual. Today, one can detect all the
similar sequences in the genome by hybridization
with a DNA probe. Such experiments have made
it clear that there are further copies of almost all
genes somewhere in the genome, although in
many cases these may be non-functional. Multigene families make biological sense in two ways.
1. Dose repetition: In the biosynthesis of almost
all proteins, one gene is sufficient for a high
rate of synthesis because of the two amplifying
effects of transcription and translation. In the
formation of different RNA types, however,
including the 5S rRNA and the different
tRNAs, the second amplifying step is missing.
Many identical genes are required in this case
to satisfy requirements. The only example of
dose repetition of a protein-coding gene is that
of the histones, which must be produced in a
short period during the cell cycle in an amount
similar to that of the DNA. Here again, the
amplifying effect of protein biosynthesis is
insufficient. Only gene duplication or multiplication in the germline is appropriate, i.e. a
process of molecular evolution that affects all
the cells of an animal. The multiplication of the
genome or of single genes can also be limited
to particular somatic cells. This also serves to
cover increased requirements for gene products but it is a process of individual biochemical adaptation and will be dealt with elsewhere
(p.27).
2. Variant repetition: When multiple genes produced by gene amplification develop independently in evolution (diversification), there arises a family of related but significantly different gene products that may be adapted to various conditions in different cell types or in different developmental stages. This book contains many such examples.
Multiple genes arise through gene duplication,
the genetic mechanism of which is most likely
unequal crossing-over. The duplicated genes are
at first arranged one after the other (a tandem
cluster); the genes of a family can also be spread
throughout the genome (dispersed genes); and
finally, there are mUlti-gene families with most of
the members together in one or more clusters and
single copies (orphons) at other positions in the
genome. This phenomenon was discovered in
1981 in the histone genes of the sea urchin Lytechinus pictus, where more than 50 orphons have
been found, but is apparently quite widespread.
In cases of dose repetition, the genes of a gene
cluster are generally regulated together and,
through particular evolutionary mechanisms
(horizontal or concerted evolution), remain similar in sequence (homogeneous). Neither of these
is valid for cases of variant repetition. Orphons
are excluded from horizontal evolution and,
therefore, show great diversification.
In all mUlti-gene families there are probably
members that are not transcribed because of the
presence of some sort of defect. Such genes are
rather misleadingly termed pseudogenes. The
name was coined in 1977 by Jacq, who discovered
the first such gene within the 5S rRNA genes of
the clawed frog, Xenopus laevis. Many pseudogenes are now recognized, e.g. in the gene families
of the globins, the immunoglobulins and the
tubulins of various mammals, cytochrome c of
rats, actin and metallothionein of man, and the
cuticula proteins of Drosophila. In some gene
families, the number of pseudogenes greatly