effect variegation on a lacZ fusion gene expressed in 
developing tissue, making possible the investiga- 
tion of this phenomenon in dividing cells. 
An aspect of the phenomenon that is becoming 
clearer is the dominance of some variegation muta- 
tions over wild type. Although variegation is always 
recessive for nearly all genes, variegated mutations 
of the brown gene are always dominant. That is, 
when the brown gene is juxtaposed to heterochro- 
matin, variable inactivation is seen for the copies in 
both cis and trans, whereas other genes are only af- 
fected in cis. Investigations in Dr. Henikoff's labora- 
tory have revealed that a necessary component of 
"trans-inactivation" of brown is somatic pairing of 
homologues. It is proposed that trans-inactivation 
results from direct contact between protein compo- 
nents responsible for the heterochromatic state of 
the cis copy of the gene and other components asso- 
ciated with the trans copy. 
In support of this model, the trans-inactivation 
phenomenon has been reproduced at sites of trans- 
posons carrying the brown gene, but only for paired 
copies of the gene. By taking advantage of the ability 
to make small deletions in vivo in the transposon 
system, it has been found that disruption of chromo- 
some pairing in the immediate vicinity of the gene 
reduces trans-inactivation, as if a cis-acting compo- 
nent of trans-inactivation is very close to or within 
the brown gene itself. Current efforts are aimed at 
mapping the precise sequence location of this cis- 
acting component, which appears to be within 
~ 1 kb of the 5' end of the coding region. 
A Somatically Unstable Chromosome 
Dr. Debora Wines has discovered a chromosome 
that shows an extreme instability in somatic cells. 
This serendipitous finding was made during a screen 
for position-effect variegation mutations: the unsta- 
ble chromosome caused gene markers carried on it 
to appear variegated. This chromosome derives 
from a translocation involving ~20% of the left arm 
of chromosome 3 and a centromere from another 
chromosome. The unstable chromosome is interme- 
diate in size among wild-type and rearranged linear 
Drosophila chromosomes, all of which are known 
to be quite stable. The instability results from ran- 
dom nondisjunction of sister chromatids during de- 
velopment, leading to clones and single cells that 
have either gained an extra copy of the chromosome 
or have lost it entirely. An intriguing possibility is 
that the defect results from a position effect on the 
centromere, suggested by the observation that ge- 
netic elements that modify position-effect variega- 
tion modify the degree of instability. This unique 
chromosome may provide a tool for the genetic 
and molecular dissection of a higher eukaryotic 
centromere. 
Homology Searching and Scoring Matrices 
Based on Protein Blocks 
A system has been developed for finding and as- 
sembling the most highly conserved regions of re- 
lated proteins for database searching. This involves 
automation of an algorithm for sensitive detection 
of multiple local alignments followed by conver- 
sion to "blocks" of aligned protein segments and 
assembly of the best set of blocks. The automated 
system was applied successively to more than 500 
groups of related proteins, yielding a database of 
about 2,000 blocks that could itself be searched for 
distant relationships. The practical use of blocks has 
been demonstrated by the detection of previously 
unknown relationships and the evaluation of rela- 
tionships proposed by others. 
A special feature of using blocks in searching is 
that more than one block from a group can be de- 
tected independently, allowing inferences of homol- 
ogy to be made with confidence based on the low 
probability of detecting multiple blocks by chance. 
Among the relationships detected with this ap- 
proach were new vertebrate and bacterial members 
of the Tel family of transposons, previously thought 
to be limited to invertebrates. 
Since the system for finding and assembling 
blocks is fully automated, the database is kept up to 
date and made available over Internet. In addition, 
an electronic mail server is maintained so that the 
current database can be searched by other re- 
searchers without requiring special software or 
hardware. 
The database of blocks was also used to derive 
amino acid substitution matrices for scoring protein 
alignments. This is a different approach from that 
used to derive the widely used matrices based on the 
Dayhoff model of evolutionary rates. This approach 
led to marked general improvements in alignments 
and in searches for homology with representatives 
from hundreds of different protein families. 
A grant from the National Institutes of Health pro- 
vided support for the project described above. 
Dr. Henikoff is also Member of the Division of 
Basic Sciences of the Fred Hutchinson Cancer Re- 
search Center, Seattle, and Affiliate Associate Pro- 
fessor in the Department of Genetics at the Univer- 
sity of Washington, Seattle. 
Articles 
Clark, D.V., and Henikoff, S. 1992. Unusual organi- 
zational features of the Drosophila Gart locus are 
GENETICS 201 
